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Al Subait A, Alghamdi RH, Ali R, Alsharidah A, Huwaizi S, Alkhodier RA, Almogren AS, Alzomia BA, Alaskar A, Boudjelal M. Discovery of PPAR Alpha Lipid Pathway Modulators That Do Not Bind Directly to the Receptor as Potential Anti-Cancer Compounds. Int J Mol Sci 2025; 26:736. [PMID: 39859448 PMCID: PMC11766124 DOI: 10.3390/ijms26020736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/17/2024] [Accepted: 12/17/2024] [Indexed: 01/30/2025] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are considered good drug targets for breast cancer because of their involvement in fatty acid metabolism that induces cell proliferation. In this study, we used the KAIMRC1 breast cancer cell line. We showed that the PPARE-Luciferase reporter gets highly activated without adding any exogenous ligand when PPAR alpha is co-transfected, and the antagonist GW6471 can inhibit the activity. Using this reporter system, we screened 240 compounds representing kinase inhibitors, epigenetic modulators, and stem cell differentiators and identified compounds that inhibit the PPARα-activated PPARE-Luciferase reporter in the KAIMRC1 cell. We selected 11 compounds (five epigenetic modulators, two stem cell differentiators, and four kinase inhibitors) that inhibited the reporter by at least 40% compared to the controls (DMSO-treated cells). We tested them in a dose-dependent manner and measured the KAIMRC1 cell viability after 48 h. All 11 compounds induced the cell killing at different IC50 values. We selected two compounds, PHA665752 and NSC3852, to dissect how they kill KAIMRC1 cells compared to the antagonist GW6741. First, molecular docking and a TR-FRET PPARα binding assay showed that compared to GW6471, these two compounds could not bind to PPARα. This means they inhibit the PPARα pathway independently rather than binding to the receptor. We further confirmed that PHA665752 and NSC3852 induce cell killing depending on the level of PPARα expression, and as such, their potency for killing the SW620 colon cancer cell line that expresses the lowest level of PPARα was less potent than for the KAIMRC1 and MDA-MB-231 cell lines. Further, using an apoptosis array and fatty acid gene expression panel, we found that both compounds regulate the PPARα pathway by controlling the genes involved in the fatty acid oxidation process. Our findings suggest that these two compounds have opposite effects involving fatty acid oxidation in the KAIMRC1 breast cancer cell line. Although we do not fully understand their mechanism of action, our data provide new insights into the potential role of these compounds in targeting breast cancer cells.
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Affiliation(s)
- Arwa Al Subait
- Medical Research Core Facility and Platforms (MRCFP)-Drug Discovery Platform, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia; (A.A.S.)
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia
| | - Raghad H. Alghamdi
- King Abdulaziz and His Companions Foundation for Giftedness and Creativity (MAWHIBA), Riyadh 11481, Saudi Arabia;
| | - Rizwan Ali
- Medical Research Core Facility and Platforms (MRCFP)-Drug Discovery Platform, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia; (A.A.S.)
| | - Amani Alsharidah
- College of Science, King Saud University, Riyadh 11459, Saudi Arabia;
| | - Sarah Huwaizi
- Medical Research Core Facility and Platforms (MRCFP)-Drug Discovery Platform, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia; (A.A.S.)
| | - Reem A. Alkhodier
- Department of Pharmaceutical Sciences, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia
| | - Aljawharah Saud Almogren
- Medical Research Core Facility and Platforms (MRCFP)-Drug Discovery Platform, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia; (A.A.S.)
| | - Barrak A. Alzomia
- Medical Research Core Facility and Platforms (MRCFP)-Drug Discovery Platform, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia; (A.A.S.)
| | - Ahmad Alaskar
- Medical Research Core Facility and Platforms (MRCFP)-Drug Discovery Platform, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia; (A.A.S.)
| | - Mohamed Boudjelal
- Medical Research Core Facility and Platforms (MRCFP)-Drug Discovery Platform, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia; (A.A.S.)
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Asgharzadeh F, Memarzia A, Alikhani V, Beigoli S, Boskabady MH. Peroxisome proliferator-activated receptors: Key regulators of tumor progression and growth. Transl Oncol 2024; 47:102039. [PMID: 38917593 PMCID: PMC11254173 DOI: 10.1016/j.tranon.2024.102039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 04/30/2024] [Accepted: 06/20/2024] [Indexed: 06/27/2024] Open
Abstract
One of the main causes of death on the globe is cancer. Peroxisome-proliferator-activated receptors (PPARs) are nuclear hormone receptors, including PPARα, PPARδ and PPARγ, which are important in regulating cancer cell proliferation, survival, apoptosis, and tumor growth. Activation of PPARs by endogenous or synthetic compounds regulates tumor progression in various tissues. Although each PPAR isotype suppresses or promotes tumor development depending on the specific tissues or ligands, the mechanism is still unclear. PPARs are receiving interest as possible therapeutic targets for a number of disorders. Numerous clinical studies are being conducted on PPARs as possible therapeutic targets for cancer. Therefore, this review will focus on the existing and future uses of PPARs agonists and antagonists in treating malignancies. PubMed, Science Direct, and Scopus databases were searched regarding the effect of PPARs on various types of cancers until the end of May 2023. The results of the review articles showed the therapeutic influence of PPARs on a wide range of cancer on in vitro, in vivo and clinical studies. However, further experimental and clinical studies are needed to be conducted on the influence of PPARs on various cancers.
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Affiliation(s)
- Fereshteh Asgharzadeh
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arghavan Memarzia
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vida Alikhani
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Sima Beigoli
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Hossein Boskabady
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Kiss DS, Toth I, Bartha T, Jerzsele A, Zsarnovszky A, Pasztine Gere E, Ondrasovicova S, Varro P, Kovago C. Effects of metal oxide inhalation on the transcription of some hormone receptors in the brain, examined in an in vivo mouse model. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2024; 31:51834-51843. [PMID: 39134792 PMCID: PMC11374873 DOI: 10.1007/s11356-024-34425-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 07/15/2024] [Indexed: 09/06/2024]
Abstract
Respirable metal oxide nanoparticles in welding fumes pose significant health risks upon inhalation, potentially leading to neurodegenerative diseases. While the exact mechanisms remain unclear, it is evident that metal oxide nanoparticles can disrupt cellular functions, including metabolism and inflammatory responses after crossing the blood-brain barrier (BBB). Our study investigates the impact of manual metal arc welding fumes on hormone receptor transcription in an in vivo mouse model. After collecting samples from six different brain regions at 24 and 96 h upon exposure, we focused on expression levels of estrogen receptors (ERs), thyroid hormone receptors (TRs), and peroxisome proliferator-activated receptors (PPARs) due to their roles in modulating neuroprotective responses and neuroinflammatory processes. Analysis revealed differential susceptibility of brain regions to hormonal disruption induced by welding fumes, with the hypothalamus (HT) and olfactory bulb (OB) showing prominent changes in receptor expression. Considering ERs, 24 h sampling showed an elevation in OB, with later increases in both ERα and ERβ. HT showed significant ERβ change only by 96 h. TRs mirrored ER patterns, with notable changes in OB and less in HT. PPARγ followed TR trends, with early upregulation in HT and downregulation elsewhere. These findings suggest a compensatory response within the CNS aimed at mitigating neuroinflammatory effects, as evidenced by the upregulation of ERβ, TRα, and PPARγ. The coordinated increase in ERs, TRs, and PPARs in the hypothalamus and olfactory bulb also highlights their potential neuroprotective roles in response to welding fume exposure. Our results also support the theory of metal oxide penetration to the CNS via the lungs-blood-BBB pathway, making HT and OB more vulnerable to welding fume exposure.
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Affiliation(s)
- David Sandor Kiss
- Department of Physiology and Biochemistry, University of Veterinary Medicine, Budapest, Hungary
| | - Istvan Toth
- Department of Physiology and Biochemistry, University of Veterinary Medicine, Budapest, Hungary.
| | - Tibor Bartha
- Department of Physiology and Biochemistry, University of Veterinary Medicine, Budapest, Hungary
| | - Akos Jerzsele
- Department of Pharmacology and Toxicology, University of Veterinary Medicine, Budapest, Hungary
| | - Attila Zsarnovszky
- Department of Physiology and Animal Health, Hungarian University of Agricultural and Life Sciences, Godollo, Hungary
- Agribiotechnology and Precision Breeding for Food Security National Laboratory, Institute of Physiology and Nutrition, Department of Physiology and Animal Health, Hungarian University of Agricultural and Life Sciences, Godollo, Hungary
| | - Erzsebet Pasztine Gere
- Department of Pharmacology and Toxicology, University of Veterinary Medicine, Budapest, Hungary
| | - Silvia Ondrasovicova
- Department of Biology and Physiology, University of Veterinary Medicine and Pharmacy in Košice, Košice, Slovakia
| | - Petra Varro
- Department of Physiology and Neurobiology, Institute of Biology, Eötvös Loránd University, Budapest, Hungary
| | - Csaba Kovago
- Department of Pharmacology and Toxicology, University of Veterinary Medicine, Budapest, Hungary
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Li WX, Xu LL, Liu CF, Dong BZ, Wang YY. Analysis of an adult diabetes mellitus caused by a rare mutation of the gene: A case report. World J Clin Cases 2024; 12:3942-3949. [PMID: 38994305 PMCID: PMC11235441 DOI: 10.12998/wjcc.v12.i19.3942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/24/2024] [Accepted: 05/11/2024] [Indexed: 06/29/2024] Open
Abstract
BACKGROUND This study presents the clinical and genetic mutation characteristics of an unusual case of adult-onset diabetes mellitus occurring in adolescence, featuring a unique mutation in the peroxisome proliferator-activated receptor gamma (PPARG) gene. Data Access Statement: Research data supporting this publication are available from the NN repository at www.NNN.org/download/. CASE SUMMARY The methodology employed entailed meticulous collection of comprehensive clinical data from the probands and their respective family members. Additionally, high-throughput sequencing was conducted to analyze the PPARG genes of the patient, her siblings, and their offspring. The results of this investigation revealed that the patient initially exhibited elevated blood glucose levels during pregnancy, accompanied by insulin resistance and hypertriglyceridemia. Furthermore, these strains displayed increased susceptibility to diabetic kidney disease without any discernible aggregation patterns. The results from the gene detection process demonstrated a heterozygous mutation of guanine (G) at position 284 in the coding region of exon 2 of PPARG, which replaced the base adenine (A) (exon2c.284A>Gp.Tyr95Cys). This missense mutation resulted in the substitution of tyrosine with cysteine at the 95th position of the translated protein. Notably, both of her siblings harbored a nucleotide heterozygous variation at the same site, and both were diagnosed with diabetes. CONCLUSION The PPARG gene mutation, particularly the p.Tyr95Cys mutation, may represent a newly identified subtype of maturity-onset diabetes of the young. This subtype is characterized by insulin resistance and lipid metabolism disorders.
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Affiliation(s)
- Wen-Xuan Li
- Department of Endocrine and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Li-Li Xu
- Department of Endocrine and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Chuan-Feng Liu
- Department of Endocrine and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Bing-Zi Dong
- Department of Endocrine and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Yun-Yang Wang
- Department of Endocrine and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
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Wei F, Hughes M, Omer M, Ngo C, Pugazhendhi AS, Kolanthai E, Aceto M, Ghattas Y, Razavi M, Kean TJ, Seal S, Coathup M. A Multifunctional Therapeutic Strategy Using P7C3 as A Countermeasure Against Bone Loss and Fragility in An Ovariectomized Rat Model of Postmenopausal Osteoporosis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308698. [PMID: 38477537 PMCID: PMC11151083 DOI: 10.1002/advs.202308698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Indexed: 03/14/2024]
Abstract
By 2060, an estimated one in four Americans will be elderly. Consequently, the prevalence of osteoporosis and fragility fractures will also increase. Presently, no available intervention definitively prevents or manages osteoporosis. This study explores whether Pool 7 Compound 3 (P7C3) reduces progressive bone loss and fragility following the onset of ovariectomy (OVX)-induced osteoporosis. Results confirm OVX-induced weakened, osteoporotic bone together with a significant gain in adipogenic body weight. Treatment with P7C3 significantly reduced osteoclastic activity, bone marrow adiposity, whole-body weight gain, and preserved bone area, architecture, and mechanical strength. Analyses reveal significantly upregulated platelet derived growth factor-BB and leukemia inhibitory factor, with downregulation of interleukin-1 R6, and receptor activator of nuclear factor kappa-B (RANK). Together, proteomic data suggest the targeting of several key regulators of inflammation, bone, and adipose turnover, via transforming growth factor-beta/SMAD, and Wingless-related integration site/be-catenin signaling pathways. To the best of the knowledge, this is first evidence of an intervention that drives against bone loss via RANK. Metatranscriptomic analyses of the gut microbiota show P7C3 increased Porphyromonadaceae bacterium, Candidatus Melainabacteria, and Ruminococcaceae bacterium abundance, potentially contributing to the favorable inflammatory, and adipo-osteogenic metabolic regulation observed. The results reveal an undiscovered, and multifunctional therapeutic strategy to prevent the pathological progression of OVX-induced bone loss.
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Affiliation(s)
- Fei Wei
- Biionix ClusterUniversity of Central FloridaOrlandoFL82816USA
| | - Megan Hughes
- School of BiosciencesCardiff UniversityWalesCF10 3ATUK
| | - Mahmoud Omer
- Biionix ClusterUniversity of Central FloridaOrlandoFL82816USA
| | - Christopher Ngo
- Biionix ClusterUniversity of Central FloridaOrlandoFL82816USA
- College of MedicineUniversity of Central FloridaOrlandoFL32827USA
| | | | - Elayaraja Kolanthai
- Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center (NSTC)University of Central FloridaOrlandoFL32826USA
| | - Matthew Aceto
- College of MedicineUniversity of Central FloridaOrlandoFL32827USA
| | - Yasmine Ghattas
- College of MedicineUniversity of Central FloridaOrlandoFL32827USA
| | - Mehdi Razavi
- Biionix ClusterUniversity of Central FloridaOrlandoFL82816USA
- College of MedicineUniversity of Central FloridaOrlandoFL32827USA
| | - Thomas J Kean
- Biionix ClusterUniversity of Central FloridaOrlandoFL82816USA
- College of MedicineUniversity of Central FloridaOrlandoFL32827USA
| | - Sudipta Seal
- Biionix ClusterUniversity of Central FloridaOrlandoFL82816USA
- College of MedicineUniversity of Central FloridaOrlandoFL32827USA
- Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center (NSTC)University of Central FloridaOrlandoFL32826USA
| | - Melanie Coathup
- Biionix ClusterUniversity of Central FloridaOrlandoFL82816USA
- College of MedicineUniversity of Central FloridaOrlandoFL32827USA
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Kim SG, Sung JY, Kang YJ, Choi HC. PPARγ activation by fisetin mitigates vascular smooth muscle cell senescence via the mTORC2-FoxO3a-autophagy signaling pathway. Biochem Pharmacol 2023; 218:115892. [PMID: 37890594 DOI: 10.1016/j.bcp.2023.115892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/23/2023] [Accepted: 10/24/2023] [Indexed: 10/29/2023]
Abstract
Cellular senescence is caused by diverse stimuli and contributes to cardiovascular diseases. Several studies have indicated that PPARγ acts as a key mediator of lipid metabolism and shown that it has a protective effect on vascular biology. Nevertheless, the mechanism responsible for the anti-aging effects of PPARγ has not been fully elucidated in vascular smooth muscle cell (VSMC). Furthermore, although mTOR complex 2 (mTORC2) is known to be involved in cellular senescence and autophagy, relatively few studies have investigated its effects as compared with mTOR complex 1 (mTORC1). Therefore, we focused on mTORC2 function and investigated the relationship between PPARγ and mTORC2, and the anti-aging mechanism in VSMC. We found PPARγ activation dose-dependently mitigated the hydrogen peroxide (H2O2)-induced senescence. Treatment of fisetin induced the translocation of PPARγ from cytosol to nuclear and inhibited VSMC senescence. Moreover, activated PPARγ increased PTEN transcription, leading to inhibition of the mTORC2 signaling pathway. We determined mTORC2 activation contributed to senescence by suppressing the FoxO3a-autophagy signaling pathway, and dual knockdown of mTORC1 and mTORC2 decreased cellular senescence and increased autophagy activation more than respective single knockdown. Finally, fisetin acted as a PPARγ activator and inhibited VSMC senescence through the mTORC2-FoxO3a-autophagy signaling pathway. These results demonstrate PPARγ is associated with cellular senescence and that fisetin has an anti-aging effect via PPARγ activation and mTORC2 inhibition in VSMC. These results demonstrate that the mTORC2 signaling pathway regulates autophagy and cellular senescence, which suggests mTORC2 should be considered a significant target for preventing cellular senescence and age-related diseases.
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Affiliation(s)
- Seul Gi Kim
- Department of Pharmacology, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu 42415, Republic of Korea; Senotherapy-based Metabolic Disease Control Research Center, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu 42415, Republic of Korea
| | - Jin Young Sung
- Department of Pharmacology, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu 42415, Republic of Korea; Senotherapy-based Metabolic Disease Control Research Center, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu 42415, Republic of Korea
| | - Young Jin Kang
- Department of Pharmacology, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu 42415, Republic of Korea
| | - Hyoung Chul Choi
- Department of Pharmacology, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu 42415, Republic of Korea; Senotherapy-based Metabolic Disease Control Research Center, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu 42415, Republic of Korea.
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Liu J, Pan Y, Liu Y, Wei W, Hu X, Xin W, Chen N. The regulation of PTEN: Novel insights into functions as cancer biomarkers and therapeutic targets. J Cell Physiol 2023; 238:1693-1715. [PMID: 37334436 DOI: 10.1002/jcp.31053] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/10/2023] [Accepted: 05/17/2023] [Indexed: 06/20/2023]
Abstract
This review summarizes the implications of the primary tumor suppressor protein phosphatase and tensin homolog (PTEN) in aggressive cancer development. PTEN interacts with other cellular proteins or factors suggesting the existence of an intricate molecular network that regulates their oncogenic function. Accumulating evidence has shown that PTEN exists and plays a role in the cytoplasmic organelles and in the nucleus. PTEN blocks phosphoinositide 3-kinases (PI3K)-protein kinase B-mammalian target of rapamycin signaling pathway by dephosphorylating phosphatidylinositol (PI)-3,4,5-triphosphate to PI-4,5-bisphosphate thus counteracting PI3K function. Studies have shown that PTEN expression is tightly regulated at transcriptional, posttranscriptional, and posttranslational levels (including protein-protein interactions and posttranslational modifications). Despite recent advances in PTEN research, the regulation and function of the PTEN gene remain largely unknown. How mutation or loss of specific exons in the PTEN gene occurs and involves in cancer development is not clear. This review illustrates the regulatory mechanisms of PTEN expression and discusses how PTEN participates in tumor development and/or suppression. Future prospects for the clinical applications are also highlighted.
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Affiliation(s)
- Jie Liu
- Department of Dermatology, Skin Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Yongli Pan
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Yuheng Liu
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Wei Wei
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Xiaoping Hu
- Department of Dermatology, Skin Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Wenqiang Xin
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Nan Chen
- Department of Gastroenterology, Liaocheng People's Hospital, Liaocheng, China
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Hwang S, Park S, Kim JH, Bang SB, Kim HJ, Ka NL, Ko Y, Kim SS, Lim GY, Lee S, Shin YK, Park SY, Kim S, Lee MO. Targeting HMG-CoA synthase 2 suppresses tamoxifen-resistant breast cancer growth by augmenting mitochondrial oxidative stress-mediated cell death. Life Sci 2023:121827. [PMID: 37276910 DOI: 10.1016/j.lfs.2023.121827] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/24/2023] [Accepted: 05/30/2023] [Indexed: 06/07/2023]
Abstract
AIMS In this study, we aimed to investigate previously unrecognized lipid metabolic perturbations in tamoxifen-resistant breast cancer (BC) by conducting comprehensive metabolomics and transcriptomics analysis. We identified the role of 3-hydroxy-3-methylglutary-coenzyme-A-synthase 2 (HMGCS2), a key enzyme responsible for ketogenesis, in tamoxifen-resistant BC growth. MAIN METHODS Comprehensive metabolomics (CE-TOFMS, LC-TOFMS) and transcriptiomics analysis were performed to characterize metabolic pathways in tamoxifen-resistant BC cells. The upregulation of HMGCS2 were verified thorugh immunohistochemistry (IHC) in clinical samples obtained from patients with recurrent BC. HMGCS2 inhibitor was discovered through surface plasmon resonance analysis, enzyme assay, and additional molecular docking studies. The effect of HMGCS2 suppression on tumor growth was studied thorugh BC xenograft model, and intratumoral lipid metabolites were analyzed via MALDI-TOFMS imaging. KEY FINDINGS We revealed that the level of HMGCS2 was highly elevated in both tamoxifen-resistant T47D sublines (T47D/TR) and clinical refractory tumor specimens from patients with ER+ breast cancer, who had been treated with adjuvant tamoxifen. Suppression of HMGCS2 in T47D/TR resulted in the accumulation of mitochondrial reactive oxygen species (mtROS) and apoptotic cell death. Further, we identified alphitolic acid, a triterpenoid natural product, as a novel HMGCS2-specific inhibitor that elevated mtROS levels and drastically retarded the growth of T47D/TR in in vitro and in vivo experiments. SIGNIFICANCE Enhanced ketogenesis with upregulation of HMGCS2 is a potential metabolic vulnerability of tamoxifen-resistant BC that offers a new therapeutic opportunity for treating patients with ER+ BC that are refractory to tamoxifen treatment.
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Affiliation(s)
- Sewon Hwang
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Soojun Park
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Jee Hyun Kim
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi, Republic of Korea
| | - Sang-Beom Bang
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea
| | - Hyeon-Ji Kim
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Na-Lee Ka
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Yoonae Ko
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Seung-Su Kim
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Ga Young Lim
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Seunghee Lee
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Young Kee Shin
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - So Yeon Park
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi, Republic of Korea.
| | - Sanghee Kim
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
| | - Mi-Ock Lee
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; Bio-MAX institute, Seoul National University, Seoul 08826, Republic of Korea.
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The Role of PPARs in Breast Cancer. Cells 2022; 12:cells12010130. [PMID: 36611922 PMCID: PMC9818187 DOI: 10.3390/cells12010130] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/07/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022] Open
Abstract
Breast cancer is a malignant tumor with high morbidity and lethality. Its pathogenesis is related to the abnormal expression of many genes. The peroxisome proliferator-activated receptors (PPARs) are a class of ligand-dependent transcription factors in the nuclear receptor superfamily. They can regulate the transcription of a large number of target genes, which are involved in life activities such as cell proliferation, differentiation, metabolism, and apoptosis, and regulate physiological processes such as glucose metabolism, lipid metabolism, inflammation, and wound healing. Further, the changes in its expression are associated with various diseases, including breast cancer. The experimental reports related to "PPAR" and "breast cancer" were retrieved from PubMed since the discovery of PPARs and summarized in this paper. This review (1) analyzed the roles and potential molecular mechanisms of non-coordinated and ligand-activated subtypes of PPARs in breast cancer progression; (2) discussed the correlations between PPARs and estrogen receptors (ERs) as the nuclear receptor superfamily; and (3) investigated the interaction between PPARs and key regulators in several signaling pathways. As a result, this paper identifies PPARs as targets for breast cancer prevention and treatment in order to provide more evidence for the synthesis of new drugs targeting PPARs or the search for new drug combination treatments.
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10
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Lin H, Han Q, Wang J, Zhong Z, Luo H, Hao Y, Jiang Y. Methylation-Mediated Silencing of RBP7 Promotes Breast Cancer Progression through PPAR and PI3K/AKT Pathway. JOURNAL OF ONCOLOGY 2022; 2022:9039110. [PMID: 36276273 PMCID: PMC9584705 DOI: 10.1155/2022/9039110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 07/06/2022] [Accepted: 09/26/2022] [Indexed: 11/17/2022]
Abstract
Retinoid-binding protein7 (RBP7) is a member of the cellular retinol-binding protein (CRBP) family, which is involved in the pathogenesis of breast cancer. The study aims to illustrate the prognostic value and the potential regulatory mechanisms of RBP7 expression in breast cancer. Bioinformatics analysis with the TCGA and CPTAC databases revealed that the mRNA and protein expression levels of RBP7 in normal were higher compared to breast cancer tissues. Survival analysis displayed that the lower expression of RBP7, the worse the prognosis in ER-positive (ER+) breast cancer patients. Genomic analysis showed that low expression of RBP7 correlates with its promoter hypermethylation in breast cancer. Functional enrichment analysis demonstrated that downregulation of RBP7 expression may exert its biological influence on breast cancer through the PPAR pathway and the PI3K/AKT pathway. In summary, we identified RBP7 as a novel biomarker that is helpful for the prognosis of ER+ breast cancer patients. Promoter methylation of RBP7 is involved in its gene silencing in breast cancer, thus regulating the occurrence and development of ER+ breast cancer through the PPAR and PI3K/AKT pathways.
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Affiliation(s)
- Hong Lin
- The fifth Clinical Medical College of Henan University of Chinese Medicine, Henan University of Chinese Medicine, No. 33 Huanghe Road, Zhengzhou, 410105 Henan, China
- Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, No. 1023, South Shatai Road, Baiyun District, Guangzhou, 510515 Guangdong, China
| | - Qizheng Han
- Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, No. 1023, South Shatai Road, Baiyun District, Guangzhou, 510515 Guangdong, China
| | - Junhao Wang
- Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, No. 1023, South Shatai Road, Baiyun District, Guangzhou, 510515 Guangdong, China
| | - Zhaoqian Zhong
- Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, No. 1023, South Shatai Road, Baiyun District, Guangzhou, 510515 Guangdong, China
| | - Haihua Luo
- Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, No. 1023, South Shatai Road, Baiyun District, Guangzhou, 510515 Guangdong, China
| | - Yibin Hao
- The fifth Clinical Medical College of Henan University of Chinese Medicine, Henan University of Chinese Medicine, No. 33 Huanghe Road, Zhengzhou, 410105 Henan, China
| | - Yong Jiang
- Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, No. 1023, South Shatai Road, Baiyun District, Guangzhou, 510515 Guangdong, China
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11
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Hermawan A, Putri H. Bioinformatics analysis reveals the potential target of rosiglitazone as an antiangiogenic agent for breast cancer therapy. BMC Genom Data 2022; 23:72. [PMID: 36114448 PMCID: PMC9482259 DOI: 10.1186/s12863-022-01086-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 09/06/2022] [Indexed: 11/19/2022] Open
Abstract
Background Several studies have demonstrated the antitumor activity of rosiglitazone (RGZ) in cancer cells, including breast cancer cells. However, the molecular targets of RGZ in the inhibition of angiogenesis in breast cancer cells remain unclear. This study aimed to explore the potential targets of RGZ in inhibiting breast cancer angiogenesis using bioinformatics-based analysis. Results Venn diagram analysis revealed 29 TR proteins. KEGG pathway enrichment analysis demonstrated that TR regulated the adipocytokine, AMPK, and PPAR signaling pathways. Oncoprint analysis showed genetic alterations in FABP4 (14%), ADIPOQ (2.9%), PPARG (2.8%), PPARGC1A (1.5%), CD36 (1.7%), and CREBBP (11%) in patients with breast cancer in a TCGA study. The mRNA levels of FABP4, ADIPOQ, PPARG, CD36, and PPARGC1A were significantly lower in patients with breast cancer than in those without breast cancer. Analysis of gene expression using bc-GenExMiner showed that the mRNA levels of FABP, ADIPOQ, PPARG, CD36, PPARGC1A, and CREBBP were significantly lower in basal-like and triple-negative breast cancer (TNBC) cells than in non-basal-like and non-TNBC cells. In general, the protein levels of these genes were low, except for that of CREBBP. Patients with breast cancer who had low mRNA levels of FABP4, ADIPOQ, PPARG, and PPARGC1A had lower overall survival rates than those with high mRNA levels, which was supported by the overall survival related to DNA methylation. Correlation analysis of immune cell infiltration with TR showed a correlation between TR and immune cell infiltration, highlighting the potential of RGZ for immunotherapy. Conclusion This study explored the potential targets of RGZ as antiangiogenic agents in breast cancer therapy and highlighted FABP4, ADIPOQ, PPARG, PPARGC1A, CD36, and CREBBP as potential targets of RGZ. These findings require further validation to explore the potential of RGZ as an antiangiogenic agent. Supplementary Information The online version contains supplementary material available at 10.1186/s12863-022-01086-2.
Recent studies have focused on the development of indirect angiogenesis inhibitors. Bioinformatics-based identification of potential rosiglitazone target genes to inhibit breast cancer angiogenesis. FABP4, ADIPOQ, PPARG, PPARGC1A, CD36, and CREBBP are potential targets of rosiglitazone.
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12
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Wagner N, Wagner KD. Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer. Cells 2022; 11:cells11152432. [PMID: 35954274 PMCID: PMC9368267 DOI: 10.3390/cells11152432] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/11/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natural ligands, PPARs are mainly focused on as targets for the treatment of metabolic syndrome and its associated complications. Nevertheless, many publications are available that implicate PPARs in malignancies. In several instances, they are controversial for very similar models. Thus, to better predict the potential use of PPAR modulators for personalized medicine in therapies against malignancies, it seems necessary and timely to review the three PPARs in relation to the didactic concept of cancer hallmark capabilities. We previously described the functions of PPAR beta/delta with respect to the cancer hallmarks and reviewed the implications of all PPARs in angiogenesis. Thus, the current review updates our knowledge on PPAR beta and the hallmarks of cancer and extends the concept to PPAR alpha and PPAR gamma.
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Affiliation(s)
- Nicole Wagner
- Correspondence: (N.W.); (K.-D.W.); Tel.: +33-489-153-713 (K.-D.W.)
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13
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Steiner BM, Berry DC. The Regulation of Adipose Tissue Health by Estrogens. Front Endocrinol (Lausanne) 2022; 13:889923. [PMID: 35721736 PMCID: PMC9204494 DOI: 10.3389/fendo.2022.889923] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/25/2022] [Indexed: 12/14/2022] Open
Abstract
Obesity and its' associated metabolic diseases such as type 2 diabetes and cardiometabolic disorders are significant health problems confronting many countries. A major driver for developing obesity and metabolic dysfunction is the uncontrolled expansion of white adipose tissue (WAT). Specifically, the pathophysiological expansion of visceral WAT is often associated with metabolic dysfunction due to changes in adipokine secretion profiles, reduced vascularization, increased fibrosis, and enrichment of pro-inflammatory immune cells. A critical determinate of body fat distribution and WAT health is the sex steroid estrogen. The bioavailability of estrogen appears to favor metabolically healthy subcutaneous fat over visceral fat growth while protecting against changes in metabolic dysfunction. Our review will focus on the role of estrogen on body fat partitioning, WAT homeostasis, adipogenesis, adipocyte progenitor cell (APC) function, and thermogenesis to control WAT health and systemic metabolism.
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Affiliation(s)
| | - Daniel C. Berry
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, United States
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14
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Issa NT, Wathieu H, Glasgow E, Peran I, Parasido E, Li T, Simbulan-Rosenthal CM, Rosenthal D, Medvedev AV, Makarov SS, Albanese C, Byers SW, Dakshanamurthy S. A novel chemo-phenotypic method identifies mixtures of salpn, vitamin D3, and pesticides involved in the development of colorectal and pancreatic cancer. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 233:113330. [PMID: 35189517 PMCID: PMC10202418 DOI: 10.1016/j.ecoenv.2022.113330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 02/01/2022] [Accepted: 02/16/2022] [Indexed: 05/24/2023]
Abstract
Environmental chemical (EC) exposures and our interactions with them has significantly increased in the recent decades. Toxicity associated biological characterization of these chemicals is challenging and inefficient, even with available high-throughput technologies. In this report, we describe a novel computational method for characterizing toxicity, associated biological perturbations and disease outcome, called the Chemo-Phenotypic Based Toxicity Measurement (CPTM). CPTM is used to quantify the EC "toxicity score" (Zts), which serves as a holistic metric of potential toxicity and disease outcome. CPTM quantitative toxicity is the measure of chemical features, biological phenotypic effects, and toxicokinetic properties of the ECs. For proof-of-concept, we subject ECs obtained from the Environmental Protection Agency's (EPA) database to the CPTM. We validated the CPTM toxicity predictions by correlating 'Zts' scores with known toxicity effects. We also confirmed the CPTM predictions with in-vitro, and in-vivo experiments. In in-vitro and zebrafish models, we showed that, mixtures of the motor oil and food additive 'Salpn' with endogenous nuclear receptor ligands such as Vitamin D3, dysregulated the nuclear receptors and key transcription pathways involved in Colorectal Cancer. Further, in a human patient derived cell organoid model, we found that a mixture of the widely used pesticides 'Tetramethrin' and 'Fenpropathrin' significantly impacts the population of patient derived pancreatic cancer cells and 3D organoid models to support rapid PDAC disease progression. The CPTM method is, to our knowledge, the first comprehensive toxico-physicochemical, and phenotypic bionetwork-based platform for efficient high-throughput screening of environmental chemical toxicity, mechanisms of action, and connection to disease outcomes.
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Affiliation(s)
- Naiem T Issa
- Department of Oncology, and Molecular and Experimental Therapeutic Research in Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Henri Wathieu
- Department of Oncology, and Molecular and Experimental Therapeutic Research in Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Eric Glasgow
- Department of Oncology, and Molecular and Experimental Therapeutic Research in Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Ivana Peran
- Department of Oncology, and Molecular and Experimental Therapeutic Research in Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Erika Parasido
- Department of Oncology, and Molecular and Experimental Therapeutic Research in Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Tianqi Li
- Department of Biochemistry and Molecular Biology, Georgetown University, Washington, DC 20057, USA
| | | | - Dean Rosenthal
- Department of Biochemistry and Molecular Biology, Georgetown University, Washington, DC 20057, USA
| | | | | | - Christopher Albanese
- Department of Oncology, and Molecular and Experimental Therapeutic Research in Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Stephen W Byers
- Department of Oncology, and Molecular and Experimental Therapeutic Research in Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA; Department of Biochemistry and Molecular Biology, Georgetown University, Washington, DC 20057, USA
| | - Sivanesan Dakshanamurthy
- Department of Oncology, and Molecular and Experimental Therapeutic Research in Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA; Department of Biochemistry and Molecular Biology, Georgetown University, Washington, DC 20057, USA.
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15
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Investigation of the Antitumor Effects of Tamoxifen and Its Ferrocene-Linked Derivatives on Pancreatic and Breast Cancer Cell Lines. Pharmaceuticals (Basel) 2022; 15:ph15030314. [PMID: 35337112 PMCID: PMC8950591 DOI: 10.3390/ph15030314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/26/2022] [Accepted: 03/02/2022] [Indexed: 12/17/2022] Open
Abstract
Tamoxifen is a long-known anti-tumor drug, which is the gold standard therapy in estrogen receptor (ER) positive breast cancer patients. According to previous studies, the conjugation of the original tamoxifen molecule with different functional groups can significantly improve its antitumor effect. The purpose of this research was to uncover the molecular mechanisms behind the cytotoxicity of different ferrocene-linked tamoxifen derivates. Tamoxifen and its ferrocene-linked derivatives, T5 and T15 were tested in PANC1, MCF7, and MDA-MB-231 cells, where the incorporation of the ferrocene group improved the cytotoxicity on all cell lines. PANC1, MCF7, and MDA-MB-231 express ERα and GPER1 (G-protein coupled ER 1). However, ERβ is only expressed by MCF7 and MDA-MB-231 cells. Tamoxifen is a known agonist of GPER1, a receptor that can promote tumor progression. Analysis of the protein expression profile showed that while being cytotoxic, tamoxifen elevated the levels of different tumor growth-promoting factors (e.g., Bcl-XL, Survivin, EGFR, Cathepsins, chemokines). On the other hand, the ferrocene-linked derivates were able to lower these proteins. Further analysis showed that the ferrocene-linked derivatives significantly elevated the cellular oxidative stress compared to tamoxifen treatment. In conclusion, we were able to find two molecules possessing better cytotoxicity compared to their unmodified parent molecule while also being able to counter the negative effects of the presence of the GPER1 through the ER-independent mechanism of oxidative stress induction.
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16
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Taylor E, Heyland A. Evolution of non-genomic nuclear receptor function. Mol Cell Endocrinol 2022; 539:111468. [PMID: 34610359 DOI: 10.1016/j.mce.2021.111468] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/01/2021] [Accepted: 09/29/2021] [Indexed: 12/18/2022]
Abstract
Nuclear receptors (NRs) are responsible for the regulation of diverse developmental and physiological systems in metazoans. NR actions can be the result of genomic and non-genomic mechanisms depending on whether they act inside or outside of the nucleus respectively. While the actions of both mechanisms have been shown to be crucial to NR functions, non-genomic actions are considered less frequently than genomic actions. Furthermore, hypotheses on the origin and evolution of non-genomic NR signaling pathways are rarely discussed in the literature. Here we summarize non-genomic NR signaling mechanisms in the context of NR protein family evolution and animal phyla. We find that NRs across groups and phyla act via calcium flux as well as protein phosphorylation cascades (MAPK/PI3K/PKC). We hypothesize and discuss a possible synapomorphy of NRs in the NR1 and NR3 families, including the thyroid hormone receptor, vitamin D receptor, ecdysone receptor, retinoic acid receptor, steroid receptors, and others. In conclusion, we propose that the advent of non-genomic NR signaling may have been a driving force behind the expansion of NR diversity in Cnidarians, Placozoans, and Bilaterians.
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Affiliation(s)
- Elias Taylor
- University of Guelph, College of Biological Sciences, Integrative Biology, Guelph, ON N1G-2W1, Canada.
| | - Andreas Heyland
- University of Guelph, College of Biological Sciences, Integrative Biology, Guelph, ON N1G-2W1, Canada.
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17
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Nuclear Receptors in Myocardial and Cerebral Ischemia-Mechanisms of Action and Therapeutic Strategies. Int J Mol Sci 2021; 22:ijms222212326. [PMID: 34830207 PMCID: PMC8617737 DOI: 10.3390/ijms222212326] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/08/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022] Open
Abstract
Nearly 18 million people died from cardiovascular diseases in 2019, of these 85% were due to heart attack and stroke. The available therapies although efficacious, have narrow therapeutic window and long list of contraindications. Therefore, there is still an urgent need to find novel molecular targets that could protect the brain and heart against ischemia without evoking major side effects. Nuclear receptors are one of the promising targets for anti-ischemic drugs. Modulation of estrogen receptors (ERs) and peroxisome proliferator-activated receptors (PPARs) by their ligands is known to exert neuro-, and cardioprotective effects through anti-apoptotic, anti-inflammatory or anti-oxidant action. Recently, it has been shown that the expression of aryl hydrocarbon receptor (AhR) is strongly increased after brain or heart ischemia and evokes an activation of apoptosis or inflammation in injury site. We hypothesize that activation of ERs and PPARs and inhibition of AhR signaling pathways could be a promising strategy to protect the heart and the brain against ischemia. In this Review, we will discuss currently available knowledge on the mechanisms of action of ERs, PPARs and AhR in experimental models of stroke and myocardial infarction and future perspectives to use them as novel targets in cardiovascular diseases.
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18
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Nelson AT, Wang Y, Nelson ER. TLX, an Orphan Nuclear Receptor With Emerging Roles in Physiology and Disease. Endocrinology 2021; 162:6360449. [PMID: 34463725 PMCID: PMC8462384 DOI: 10.1210/endocr/bqab184] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Indexed: 12/14/2022]
Abstract
TLX (NR2E1), an orphan member of the nuclear receptor superfamily, is a transcription factor that has been described to be generally repressive in nature. It has been implicated in several aspects of physiology and disease. TLX is best known for its ability to regulate the proliferation of neural stem cells and retinal progenitor cells. Dysregulation, overexpression, or loss of TLX expression has been characterized in numerous studies focused on a diverse range of pathological conditions, including abnormal brain development, psychiatric disorders, retinopathies, metabolic disease, and malignant neoplasm. Despite the lack of an identified endogenous ligand, several studies have described putative synthetic and natural TLX ligands, suggesting that this receptor may serve as a therapeutic target. Therefore, this article aims to briefly review what is known about TLX structure and function in normal physiology, and provide an overview of TLX in regard to pathological conditions. Particular emphasis is placed on TLX and cancer, and the potential utility of this receptor as a therapeutic target.
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Affiliation(s)
- Adam T Nelson
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Yu Wang
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Erik R Nelson
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA
- University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, Illinois 60612, USA
- Carl R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People Theme, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA
- Correspondence: Erik R. Nelson, PhD, Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 407 S Goodwin Ave (MC-114), Urbana, IL 61801, USA.
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19
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Liu S, Knochelmann HM, Lomeli SH, Hong A, Richardson M, Yang Z, Lim RJ, Wang Y, Dumitras C, Krysan K, Timmers C, Romeo MJ, Krieg C, O’Quinn EC, Horton JD, Dubinett SM, Paulos CM, Neskey DM, Lo RS. Response and recurrence correlates in individuals treated with neoadjuvant anti-PD-1 therapy for resectable oral cavity squamous cell carcinoma. Cell Rep Med 2021; 2:100411. [PMID: 34755131 PMCID: PMC8561238 DOI: 10.1016/j.xcrm.2021.100411] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/06/2021] [Accepted: 09/20/2021] [Indexed: 01/19/2023]
Abstract
Neoadjuvant PD-1 blockade may be efficacious in some individuals with high-risk, resectable oral cavity head and neck cancer. To explore correlates of response patterns to neoadjuvant nivolumab treatment and post-surgical recurrences, we analyzed longitudinal tumor and blood samples in a cohort of 12 individuals displaying 33% responsiveness. Pretreatment tumor-based detection of FLT4 mutations and PTEN signature enrichment favors response, and high tumor mutational burden improves recurrence-free survival. In contrast, preexisting and/or acquired mutations (in CDKN2A, YAP1, or JAK2) correlate with innate resistance and/or tumor recurrence. Immunologically, tumor response after therapy entails T cell receptor repertoire diversification in peripheral blood and intratumoral expansion of preexisting T cell clones. A high ratio of regulatory T to T helper 17 cells in pretreatment blood predicts low T cell receptor repertoire diversity in pretreatment blood, a low cytolytic T cell signature in pretreatment tumors, and innate resistance. Our study provides a molecular framework to advance neoadjuvant anti-PD-1 therapy for individuals with resectable head and neck cancer.
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MESH Headings
- Antineoplastic Agents, Immunological/therapeutic use
- Carcinoma, Squamous Cell/drug therapy
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/immunology
- Carcinoma, Squamous Cell/surgery
- Cyclin-Dependent Kinase Inhibitor p16/genetics
- Cyclin-Dependent Kinase Inhibitor p16/immunology
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Immune Checkpoint Inhibitors/therapeutic use
- Janus Kinase 2/genetics
- Janus Kinase 2/immunology
- Mouth Neoplasms/drug therapy
- Mouth Neoplasms/genetics
- Mouth Neoplasms/immunology
- Mouth Neoplasms/surgery
- Mutation
- Neoadjuvant Therapy/methods
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/surgery
- Nivolumab/therapeutic use
- PTEN Phosphohydrolase/genetics
- PTEN Phosphohydrolase/immunology
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- Programmed Cell Death 1 Receptor/genetics
- Programmed Cell Death 1 Receptor/immunology
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- Receptors, Antigen, T-Cell, alpha-beta/immunology
- Survival Analysis
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/pathology
- Th17 Cells/drug effects
- Th17 Cells/immunology
- Th17 Cells/pathology
- Treatment Outcome
- Vascular Endothelial Growth Factor Receptor-3/genetics
- Vascular Endothelial Growth Factor Receptor-3/immunology
- YAP-Signaling Proteins/genetics
- YAP-Signaling Proteins/immunology
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Affiliation(s)
- Sixue Liu
- Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Hannah M. Knochelmann
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Shirley H. Lomeli
- Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Aayoung Hong
- Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Mary Richardson
- Department of Pathology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Zhentao Yang
- Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Raymond J. Lim
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Yan Wang
- Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Camelia Dumitras
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Kostyantyn Krysan
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | | | - Martin J. Romeo
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Carsten Krieg
- Department of Immunology and Microbiology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Elizabeth C. O’Quinn
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Joshua D. Horton
- Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Steve M. Dubinett
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Chrystal M. Paulos
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
- Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA
| | - David M. Neskey
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Roger S. Lo
- Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
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20
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Lewoniewska S, Oscilowska I, Huynh TYL, Prokop I, Baszanowska W, Bielawska K, Palka J. Troglitazone-Induced PRODH/POX-Dependent Apoptosis Occurs in the Absence of Estradiol or ERβ in ER-Negative Breast Cancer Cells. J Clin Med 2021; 10:jcm10204641. [PMID: 34682765 PMCID: PMC8538344 DOI: 10.3390/jcm10204641] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/28/2021] [Accepted: 10/08/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary PRODH/POX (proline dehydrogenase/proline oxidase) is a mitochondrial enzyme that catalyzes proline degradation generating reactive oxygen species (ROS). Estrogens limit proline availability for PRODH/POX by stimulating collagen biosynthesis. It has been considered that estrogens determine efficiency of troglitazone (TGZ)-induced PRODH/POX-dependent apoptosis in breast cancer cells. The studies were performed in wild-type and PRODH/POX-silenced estrogen-dependent MCF-7 cells and estrogen-independent MDA-MB-231 cells. DNA and collagen biosynthesis were determined by radiometric method, ROS production was measured by fluorescence assay, protein expression was determined by Western blot and proline concentration by LC/MS analysis. We found that: i/TGZ-induced apoptosis in MDA-MB-231 occurs only in the absence of estradiol or ERβ, ii/the process is mediated by PRODH/POX, iii/and is facilitated by proline availability for PRODH/POX by TGZ-dependent inhibition of collagen biosynthesis (proline utilizing process). The data suggest that combined TGZ and anti-estrogen treatment could be considered in experimental therapy of ER negative breast cancers. Abstract The impact of estradiol on troglitazone (TGZ)-induced proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis was studied in wild-type and PRODH/POX-silenced estrogen receptor (ER) dependent MCF-7 cells and ER-independent MDA-MB-231 cells. DNA and collagen biosynthesis were determined by radiometric method, prolidase activity evaluated by colorimetric method, ROS production was measured by fluorescence assay. Protein expression was determined by Western blot and proline concentration by LC/MS analysis. PRODH/POX degrades proline yielding reactive oxygen species (ROS). Estrogens stimulate collagen biosynthesis utilizing free proline and limiting its availability for PRODH/POX-dependent apoptosis. TGZ cytotoxicity was highly pronounced in wild-type MDA-MB-231 cells cultured in medium without estradiol or in the cells cultured in medium with estradiol but deprived of ERβ (by ICI-dependent degradation), while in PRODH/POX-silenced cells the process was not affected. The TGZ cytotoxicity was accompanied by increase in PRODH/POX expression, ROS production, expression of cleaved caspase-3, caspase-9 and PARP, inhibition of collagen biosynthesis, prolidase activity and decrease in intracellular proline concentration. The phenomena were not observed in PRODH/POX-silenced cells. The data suggest that TGZ-induced apoptosis in MDA-MB-231 cells cultured in medium without estradiol or deprived of ERβ is mediated by PRODH/POX and the process is facilitated by proline availability for PRODH/POX by TGZ-dependent inhibition of collagen biosynthesis. It suggests that combined TGZ and antiestrogen treatment could be considered in experimental therapy of estrogen receptor negative breast cancers.
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Affiliation(s)
- Sylwia Lewoniewska
- Department of Medicinal Chemistry, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland; (S.L.); (T.Y.L.H.); (I.P.); (W.B.); (K.B.)
| | - Ilona Oscilowska
- Department of Analysis and Bioanalysis of Medicines, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland;
| | - Thi Yen Ly Huynh
- Department of Medicinal Chemistry, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland; (S.L.); (T.Y.L.H.); (I.P.); (W.B.); (K.B.)
| | - Izabela Prokop
- Department of Medicinal Chemistry, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland; (S.L.); (T.Y.L.H.); (I.P.); (W.B.); (K.B.)
| | - Weronika Baszanowska
- Department of Medicinal Chemistry, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland; (S.L.); (T.Y.L.H.); (I.P.); (W.B.); (K.B.)
| | - Katarzyna Bielawska
- Department of Medicinal Chemistry, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland; (S.L.); (T.Y.L.H.); (I.P.); (W.B.); (K.B.)
| | - Jerzy Palka
- Department of Medicinal Chemistry, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland; (S.L.); (T.Y.L.H.); (I.P.); (W.B.); (K.B.)
- Correspondence: ; Tel.: +48-85-748-5706
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21
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Loo SY, Syn NL, Koh APF, Teng JCF, Deivasigamani A, Tan TZ, Thike AA, Vali S, Kapoor S, Wang X, Wang JW, Tan PH, Yip GW, Sethi G, Huang RYJ, Hui KM, Wang L, Goh BC, Kumar AP. Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers. Cell Death Discov 2021; 7:265. [PMID: 34580286 PMCID: PMC8476547 DOI: 10.1038/s41420-021-00635-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 08/23/2021] [Accepted: 09/03/2021] [Indexed: 01/04/2023] Open
Abstract
Clinical trials repurposing peroxisome proliferator-activated receptor-gamma (PPARγ) agonists as anticancer agents have exhibited lackluster efficacy across a variety of tumor types. Here, we report that increased PPARG expression is associated with a better prognosis but is anticorrelated with histone deacetylase (HDAC) 1 and 2 expressions. We show that HDAC overexpression blunts anti-proliferative and anti-angiogenic responses to PPARγ agonists via transcriptional and post-translational mechanisms, however, these can be neutralized with clinically approved and experimental HDAC inhibitors. Supporting this notion, concomitant treatment with HDAC inhibitors was required to license the tumor-suppressive effects of PPARγ agonists in triple-negative and endocrine-refractory breast cancer cells, and combination therapy also restrained angiogenesis in a tube formation assay. This combination was also synergistic in estrogen receptor-alpha (ERα)-positive cells because HDAC blockade abrogated ERα interference with PPARγ-regulated transcription. Following a pharmacokinetics optimization study, the combination of rosiglitazone and a potent pan-HDAC inhibitor, LBH589, stalled disease progression in a mouse model of triple-negative breast cancer greater than either of the monotherapies, while exhibiting a favorable safety profile. Our findings account for historical observations of de-novo resistance to PPARγ agonist monotherapy and propound a therapeutically cogent intervention against two aggressive breast cancer subtypes.
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Affiliation(s)
- Ser Yue Loo
- Cancer Science Institute of Singapore and Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Genome Institute of Singapore, A*STAR, Singapore, Singapore
| | - Nicholas L Syn
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Angele Pei-Fern Koh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Janet Cheng-Fei Teng
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Amudha Deivasigamani
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Aye Aye Thike
- Department of Pathology, Singapore General Hospital, Singapore, Singapore
| | - Shireen Vali
- Cellworks Research India Pvt. Ltd., Bengaluru, India
| | - Shweta Kapoor
- Cellworks Research India Pvt. Ltd., Bengaluru, India
| | - Xiaoyuan Wang
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Cardiovascular Research Institute (CVRI), National University Heart Centre, Singapore (NUHCS), National University Health System, Singapore, Singapore
| | - Jiong Wei Wang
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Puay Hoon Tan
- Department of Pathology, Singapore General Hospital, Singapore, Singapore
| | - George W Yip
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ruby Yun-Ju Huang
- School of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Kam Man Hui
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Lingzhi Wang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Boon Cher Goh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.,Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,National University Cancer Institute, National University Health System, Singapore, Singapore.,Department of Haematology-Oncology, National University Hospital, National University Health System, Singapore, Singapore
| | - Alan Prem Kumar
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. .,NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,National University Cancer Institute, National University Health System, Singapore, Singapore.
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22
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Saxena A, Mathur N, Tiwari P, Mathur SK. Whole transcriptome RNA-seq reveals key regulatory factors involved in type 2 diabetes pathology in peripheral fat of Asian Indians. Sci Rep 2021; 11:10632. [PMID: 34017037 PMCID: PMC8137704 DOI: 10.1038/s41598-021-90148-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 05/06/2021] [Indexed: 01/04/2023] Open
Abstract
The prevalence of Type 2 Diabetes has reached an epidemic proportion particularly in south Asian countries. We have earlier shown that the anatomical fat distribution, termed 'thin fat phenotype' in this population indeed plays a major role for their T2D-predisposition it is indeed the sick fat or adiposopathy, which is the root cause of metabolic syndrome and diabetes and affects both-peripheral, as well as visceral adipose tissue compartments. In present study, we have attempted to unravel the altered regulatory mechanisms at the level of transcription factors, and miRNAs those may likely accounts to T2D pathophysiology in femoral subcutaneous adipose tissue. We prioritized transcription factors and protein kinases as likely upstream regulators of obtained differentially expressed genes in this RNA-seq study. An inferred network of these upstream regulators was then derived and the role of TFs and miRNAs in T2D pathophysiology was explored. In conclusions, this RNS-Seq study finds that peripheral subcutaneous adipose tissue among Asian Indians show pathology characterized by altered lipid, glucose and protein metabolism, adipogenesis defect and inflammation. A network of regulatory transcription factors, protein kinases and microRNAs have been imputed which converge on the process of adipogenesis. As the majority of these genes also showed altered expression in diabetics and some of them are also circulatory, therefore they deserve further investigation for potential clinical diagnostic and therapeutic applications.
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Affiliation(s)
- Aditya Saxena
- Department of Computer Engineering and Applications, Institute of Engineering and Technology, GLA University, Mathura, 281406, India
| | - Nitish Mathur
- Department of Endocrinology, Sawai Man Singh Medical College and Hospital, Jaipur, 302004, India
| | - Pradeep Tiwari
- Department of Endocrinology, Sawai Man Singh Medical College and Hospital, Jaipur, 302004, India
- Department of Chemistry, School of Basic Sciences, Manipal University Jaipur, Jaipur, 303007, India
| | - Sandeep Kumar Mathur
- Department of Endocrinology, Sawai Man Singh Medical College and Hospital, Jaipur, 302004, India.
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23
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Stewart AN, Lowe JL, Glaser EP, Mott CA, Shahidehpour RK, McFarlane KE, Bailey WM, Zhang B, Gensel JC. Acute inflammatory profiles differ with sex and age after spinal cord injury. J Neuroinflammation 2021; 18:113. [PMID: 33985529 PMCID: PMC8120918 DOI: 10.1186/s12974-021-02161-8] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 04/29/2021] [Indexed: 01/05/2023] Open
Abstract
Background Sex and age are emerging as influential variables that affect spinal cord injury (SCI) recovery. Despite a changing demographic towards older age at the time of SCI, the effects of sex or age on inflammation remain to be elucidated. This study determined the sex- and age-dependency of the innate immune response acutely after SCI. Methods Male and female mice of ages 4- and 14-month-old received T9 contusion SCI and the proportion of microglia, monocyte-derived macrophages (MDM), and neutrophils surrounding the lesion were determined at 3- and 7-day post-injury (DPI) using flow cytometry. Cell counts of microglia and MDMs were obtained using immunohistochemistry to verify flow cytometry results at 3-DPI. Microglia and MDMs were separately isolated using fluorescence-activated cell sorting (FACS) at 3-day post-injury (DPI) to assess RNA expression of 27 genes associated with activation, redox, and debris metabolism/clearance. Results Flow cytometry revealed that being female and older at the time of injury significantly increased MDMs relative to other phagocytes, specifically increasing the ratio of MDMs to microglia at 3-DPI. Cell counts using immunohistochemistry revealed that male mice have more total microglia within SCI lesions that can account for a lower MDM/microglia ratio. With NanoString analyses of 27 genes, only 1 was differentially expressed between sexes in MDMs; specifically, complement protein C1qa was increased in males. No genes were affected by age in MDMs. Only 2 genes were differentially regulated in microglia between sexes after controlling for false discovery rate, specifically CYBB (NOX2) as a reactive oxygen species (ROS)-associated marker as well as MRC1 (CD206), a gene associated with reparative phenotypes. Both genes were increased in female microglia. No microglial genes were differentially regulated between ages. Differences between microglia and MDMs were found in 26 of 27 genes analyzed, all expressed higher in MDMs with three exceptions. Specifically, C1qa, cPLA2, and CD86 were expressed higher in microglia. Conclusions These findings indicate that inflammatory responses to SCI are sex-dependent at both the level of cellular recruitment and gene expression. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02161-8.
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Affiliation(s)
- Andrew N Stewart
- Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - John L Lowe
- Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.,Science Honors Program of Georgetown College, Georgetown, KY, 40324, USA
| | - Ethan P Glaser
- Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Caitlin A Mott
- Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Ryan K Shahidehpour
- Department of Neuroscience, Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Katelyn E McFarlane
- Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - William M Bailey
- Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Bei Zhang
- Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.,Present address: Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10021, USA
| | - John C Gensel
- Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
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24
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Augimeri G, Bonofiglio D. PPARgamma: A Potential Intrinsic and Extrinsic Molecular Target for Breast Cancer Therapy. Biomedicines 2021; 9:biomedicines9050543. [PMID: 34067944 PMCID: PMC8152061 DOI: 10.3390/biomedicines9050543] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/01/2021] [Accepted: 05/10/2021] [Indexed: 02/07/2023] Open
Abstract
Over the last decades, the breast tumor microenvironment (TME) has been increasingly recognized as a key player in tumor development and progression and as a promising prognostic and therapeutic target for breast cancer patients. The breast TME, representing a complex network of cellular signaling—deriving from different stromal cell types as well as extracellular matrix components, extracellular vesicles, and soluble growth factors—establishes a crosstalk with cancer cells sustaining tumor progression. A significant emphasis derives from the tumor surrounding inflammation responsible for the failure of the immune system to effectively restrain breast cancer growth. Thus, effective therapeutic strategies require a deeper understanding of the interplay between tumor and stroma, aimed at targeting both the intrinsic neoplastic cells and the extrinsic surrounding stroma. In this scenario, peroxisome proliferator-activated receptor (PPAR) γ, primarily known as a metabolic regulator, emerged as a potential target for breast cancer treatment since it functions in breast cancer cells and several components of the breast TME. In particular, the activation of PPARγ by natural and synthetic ligands inhibits breast cancer cell growth, motility, and invasiveness. Moreover, activated PPARγ may educate altered stromal cells, counteracting the pro-inflammatory milieu that drive breast cancer progression. Interestingly, using Kaplan–Meier survival curves, PPARγ also emerges as a prognostically favorable factor in breast cancer patients. In this perspective, we briefly discuss the mechanisms by which PPARγ is implicated in tumor biology as well as in the complex regulatory networks within the breast TME. This may help to profile approaches that provide a simultaneous inhibition of epithelial cells and TME components, offering a more efficient way to treat breast cancer.
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25
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Khamehiee N, Jazireian P, Ebrahimi B, Alizadeh A, Shahhoseini M. Paternal trans-fatty acid and vitamin E diet affects rat offspring's semen quality and PPARs expression. Andrologia 2021; 53:e14082. [PMID: 33905135 DOI: 10.1111/and.14082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 02/28/2021] [Accepted: 04/09/2021] [Indexed: 11/29/2022] Open
Abstract
Trans-fatty acids (TFAs) consumption has created concerns regarding male/female reproductive system. However, the effects of TFA in paternal diet on offspring's reproduction have not been addressed. The purpose of this study is to investigate the effects of rat paternal TFAs and vitamin E consumption on offspring's sperm quality and expression pattern of peroxisome proliferator-activated receptors (PPARs) in testis tissues. Forty adult male rats were randomly divided into four groups: Control diet (C); Control diet plus TFA (CTH); diet supplemented with vitamin E (E) and a diet containing vitamin E and TFA (ETH). Mother rats had normal diet during gestation period. Three offspring from each group were chosen randomly and their testicular samples were collected, and sperm parameters were measured by CASA. Our results indicate that feeding fathers with TFA can negatively affect offspring's sperm concentration and motility, while consumption of vitamin E can improve these parameters (p < .05). The paternal diet containing TFA down-regulated the expression of PPARβ and PPARγ genes, whereas vitamin E-containing diet up-regulated the transcription of PPAR genes. In conclusion, TFA intake in paternal diet may have negative effects on reproductive system of the offspring while vitamin E may not diminish these effects.
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Affiliation(s)
- Narges Khamehiee
- Department of Genetics, Tehran Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Parham Jazireian
- Department of Genetics, Reproductive Biomedicine Research Centre, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Bita Ebrahimi
- Department of Embryology, Reproductive Biomedicine Research Centre, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - AliReza Alizadeh
- Department of Embryology, Reproductive Biomedicine Research Centre, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Maryam Shahhoseini
- Department of Genetics, Reproductive Biomedicine Research Centre, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.,Reproductive Epidemiology Research Centre, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.,Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
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26
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Palka J, Oscilowska I, Szoka L. Collagen metabolism as a regulator of proline dehydrogenase/proline oxidase-dependent apoptosis/autophagy. Amino Acids 2021; 53:1917-1925. [PMID: 33818628 PMCID: PMC8651534 DOI: 10.1007/s00726-021-02968-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/19/2021] [Indexed: 12/21/2022]
Abstract
Recent studies on the regulatory role of amino acids in cell metabolism have focused on the functional significance of proline degradation. The process is catalysed by proline dehydrogenase/proline oxidase (PRODH/POX), a mitochondrial flavin-dependent enzyme converting proline into ∆1-pyrroline-5-carboxylate (P5C). During this process, electrons are transferred to electron transport chain producing ATP for survival or they directly reduce oxygen, producing reactive oxygen species (ROS) inducing apoptosis/autophagy. However, the mechanism for switching survival/apoptosis mode is unknown. Although PRODH/POX activity and energetic metabolism were suggested as an underlying mechanism for the survival/apoptosis switch, proline availability for this enzyme is also important. Proline availability is regulated by prolidase (proline supporting enzyme), collagen biosynthesis (proline utilizing process) and proline synthesis from glutamine, glutamate, α-ketoglutarate (α-KG) and ornithine. Proline availability is dependent on the rate of glycolysis, TCA and urea cycles, proline metabolism, collagen biosynthesis and its degradation. It is well established that proline synthesis enzymes, P5C synthetase and P5C reductase as well as collagen prolyl hydroxylases are up-regulated in most of cancer types and control rates of collagen biosynthesis. Up-regulation of collagen prolyl hydroxylase and its exhaustion of ascorbate and α-KG may compete with DNA and histone demethylases (that require the same cofactors) to influence metabolic epigenetics. This knowledge led us to hypothesize that up-regulation of prolidase and PRODH/POX with inhibition of collagen biosynthesis may represent potential pharmacotherapeutic approach to induce apoptosis or autophagic death in cancer cells. These aspects of proline metabolism are discussed in the review as an approach to understand complex regulatory mechanisms driving PRODH/POX-dependent apoptosis/survival.
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Affiliation(s)
- Jerzy Palka
- Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok, Poland
| | - Ilona Oscilowska
- Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok, Poland
| | - Lukasz Szoka
- Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok, Poland
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27
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Estrogen and Glycemic Homeostasis: The Fundamental Role of Nuclear Estrogen Receptors ESR1/ESR2 in Glucose Transporter GLUT4 Regulation. Cells 2021; 10:cells10010099. [PMID: 33430527 PMCID: PMC7827878 DOI: 10.3390/cells10010099] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/03/2021] [Accepted: 01/04/2021] [Indexed: 02/07/2023] Open
Abstract
Impaired circulating estrogen levels have been related to impaired glycemic homeostasis and diabetes mellitus (DM), both in females and males. However, for the last twenty years, the relationship between estrogen, glycemic homeostasis and the mechanisms involved has remained unclear. The characterization of estrogen receptors 1 and 2 (ESR1 and ESR2) and of insulin-sensitive glucose transporter type 4 (GLUT4) finally offered a great opportunity to shed some light on estrogen regulation of glycemic homeostasis. In this manuscript, we review the relationship between estrogen and DM, focusing on glycemic homeostasis, estrogen, ESR1/ESR2 and GLUT4. We review glycemic homeostasis and GLUT4 expression (muscle and adipose tissues) in Esr1−/− and Esr2−/− transgenic mice. We specifically address estradiol-induced and ESR1/ESR2-mediated regulation of the solute carrier family 2 member 4 (Slc2a4) gene, examining ESR1/ESR2-mediated genomic mechanisms that regulate Slc2a4 transcription, especially those occurring in cooperation with other transcription factors. In addition, we address the estradiol-induced translocation of ESR1 and GLUT4 to the plasma membrane. Studies make it clear that ESR1-mediated effects are beneficial, whereas ESR2-mediated effects are detrimental to glycemic homeostasis. Thus, imbalance of the ESR1/ESR2 ratio may have important consequences in metabolism, highlighting that ESR2 hyperactivity assumes a diabetogenic role.
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28
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Gong S, Han X, Li M, Cai X, Liu W, Luo Y, Zhang SM, Zhou L, Ma Y, Huang X, Li Y, Zhou X, Zhu Y, Wang Q, Chen L, Ren Q, Zhang P, Ji L. Genetics and Clinical Characteristics of PPARγ Variant-Induced Diabetes in a Chinese Han Population. Front Endocrinol (Lausanne) 2021; 12:677130. [PMID: 34764936 PMCID: PMC8576343 DOI: 10.3389/fendo.2021.677130] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 10/06/2021] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVES PPARγ variants cause lipodystrophy, insulin resistance, and diabetes. This study aimed to determine the relationship between PPARγ genotypes and phenotypes and to explore the pathogenesis of diabetes beyond this relationship. METHODS PPARγ2 exons in 1,002 Chinese patients with early-onset type 2 diabetes (diagnosed before 40 years of age) were sequenced. The functions of variants were evaluated by in vitro assays. Additionally, a review of the literature was performed to obtain all reported cases with rare PPARγ2 variants to evaluate the characteristics of variants in different functional domains. RESULTS Six (0.6%) patients had PPARγ2 variant-induced diabetes (PPARG-DM) in the early-onset type 2 diabetes group, including three with the p.Tyr95Cys variant in activation function 1 domain (AF1), of which five patients (83%) had diabetic kidney disease (DKD). Functional experiments showed that p.Tyr95Cys suppresses 3T3-L1 preadipocyte differentiation. A total of 64 cases with damaging rare variants were reported previously. Patients with rare PPARγ2 variants in AF1 of PPARγ2 had a lower risk of lipodystrophy and a higher rate of obesity than those with variants in other domains, as confirmed in patients identified in this study. CONCLUSION The prevalence of PPARG-DM is similar in Caucasian and Chinese populations, and DKD was often observed in these patients. Patients with variants in the AF1 of PPARγ2 had milder clinical phenotypes and lack typical lipodystrophy features than those with variants in other domains. Our findings emphasize the importance of screening such patients via genetic testing and suggest that thiazolidinediones might be a good choice for these patients.
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Affiliation(s)
- Siqian Gong
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
| | - Xueyao Han
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
- *Correspondence: Linong Ji, ; Xueyao Han,
| | - Meng Li
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
| | - Wei Liu
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
| | - Yingying Luo
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
| | - Si-min Zhang
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
| | - Lingli Zhou
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
| | - Yumin Ma
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
| | - Xiuting Huang
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
| | - Yufeng Li
- Department of Endocrinology, Beijing Pinggu District Hospital, Beijing, China
| | - Xianghai Zhou
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
| | - Yu Zhu
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
| | - Qiuping Wang
- Department of Endocrinology, Beijing Liangxiang Hospital, Beijing, China
| | - Ling Chen
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
| | - Qian Ren
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
| | - Ping Zhang
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing, China
- *Correspondence: Linong Ji, ; Xueyao Han,
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Augimeri G, Gelsomino L, Plastina P, Giordano C, Barone I, Catalano S, Andò S, Bonofiglio D. Natural and Synthetic PPARγ Ligands in Tumor Microenvironment: A New Potential Strategy against Breast Cancer. Int J Mol Sci 2020; 21:E9721. [PMID: 33352766 PMCID: PMC7767156 DOI: 10.3390/ijms21249721] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/15/2020] [Accepted: 12/18/2020] [Indexed: 12/19/2022] Open
Abstract
Multiple lines of evidence indicate that activation of the peroxisome proliferator-activated receptor γ (PPARγ) by natural or synthetic ligands exerts tumor suppressive effects in different types of cancer, including breast carcinoma. Over the past decades a new picture of breast cancer as a complex disease consisting of neoplastic epithelial cells and surrounding stroma named the tumor microenvironment (TME) has emerged. Indeed, TME is now recognized as a pivotal element for breast cancer development and progression. Novel strategies targeting both epithelial and stromal components are under development or undergoing clinical trials. In this context, the aim of the present review is to summarize PPARγ activity in breast TME focusing on the role of this receptor on both epithelial/stromal cells and extracellular matrix components of the breast cancer microenvironment. The information provided from the in vitro and in vivo research indicates PPARγ ligands as potential agents with regards to the battle against breast cancer.
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Affiliation(s)
- Giuseppina Augimeri
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (L.G.); (P.P.); (C.G.); (I.B.); (S.C.); (S.A.)
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Luca Gelsomino
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (L.G.); (P.P.); (C.G.); (I.B.); (S.C.); (S.A.)
| | - Pierluigi Plastina
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (L.G.); (P.P.); (C.G.); (I.B.); (S.C.); (S.A.)
| | - Cinzia Giordano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (L.G.); (P.P.); (C.G.); (I.B.); (S.C.); (S.A.)
- Centro Sanitario, University of Calabria, 87036 Arcavacata di Rende (CS), Italy
| | - Ines Barone
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (L.G.); (P.P.); (C.G.); (I.B.); (S.C.); (S.A.)
- Centro Sanitario, University of Calabria, 87036 Arcavacata di Rende (CS), Italy
| | - Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (L.G.); (P.P.); (C.G.); (I.B.); (S.C.); (S.A.)
- Centro Sanitario, University of Calabria, 87036 Arcavacata di Rende (CS), Italy
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (L.G.); (P.P.); (C.G.); (I.B.); (S.C.); (S.A.)
- Centro Sanitario, University of Calabria, 87036 Arcavacata di Rende (CS), Italy
| | - Daniela Bonofiglio
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (L.G.); (P.P.); (C.G.); (I.B.); (S.C.); (S.A.)
- Centro Sanitario, University of Calabria, 87036 Arcavacata di Rende (CS), Italy
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Augimeri G, Giordano C, Gelsomino L, Plastina P, Barone I, Catalano S, Andò S, Bonofiglio D. The Role of PPARγ Ligands in Breast Cancer: From Basic Research to Clinical Studies. Cancers (Basel) 2020; 12:cancers12092623. [PMID: 32937951 PMCID: PMC7564201 DOI: 10.3390/cancers12092623] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/11/2020] [Accepted: 09/12/2020] [Indexed: 02/06/2023] Open
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ), belonging to the nuclear receptor superfamily, is a ligand-dependent transcription factor involved in a variety of pathophysiological conditions such as inflammation, metabolic disorders, cardiovascular disease, and cancers. In this latter context, PPARγ is expressed in many tumors including breast cancer, and its function upon binding of ligands has been linked to the tumor development, progression, and metastasis. Over the last decade, much research has focused on the potential of natural agonists for PPARγ including fatty acids and prostanoids that act as weak ligands compared to the strong and synthetic PPARγ agonists such as thiazolidinedione drugs. Both natural and synthetic compounds have been implicated in the negative regulation of breast cancer growth and progression. The aim of the present review is to summarize the role of PPARγ activation in breast cancer focusing on the underlying cellular and molecular mechanisms involved in the regulation of cell proliferation, cell cycle, and cell death, in the modulation of motility and invasion as well as in the cross-talk with other different signaling pathways. Besides, we also provide an overview of the in vivo breast cancer models and clinical studies. The therapeutic effects of natural and synthetic PPARγ ligands, as antineoplastic agents, represent a fascinating and clinically a potential translatable area of research with regards to the battle against cancer.
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Affiliation(s)
- Giuseppina Augimeri
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (C.G.); (L.G.); (P.P.); (I.B.); (S.C.); (S.A.)
| | - Cinzia Giordano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (C.G.); (L.G.); (P.P.); (I.B.); (S.C.); (S.A.)
- Centro Sanitario, University of Calabria, 87036 Arcavacata di Rende (CS), Italy
| | - Luca Gelsomino
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (C.G.); (L.G.); (P.P.); (I.B.); (S.C.); (S.A.)
| | - Pierluigi Plastina
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (C.G.); (L.G.); (P.P.); (I.B.); (S.C.); (S.A.)
| | - Ines Barone
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (C.G.); (L.G.); (P.P.); (I.B.); (S.C.); (S.A.)
- Centro Sanitario, University of Calabria, 87036 Arcavacata di Rende (CS), Italy
| | - Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (C.G.); (L.G.); (P.P.); (I.B.); (S.C.); (S.A.)
- Centro Sanitario, University of Calabria, 87036 Arcavacata di Rende (CS), Italy
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (C.G.); (L.G.); (P.P.); (I.B.); (S.C.); (S.A.)
| | - Daniela Bonofiglio
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy; (G.A.); (C.G.); (L.G.); (P.P.); (I.B.); (S.C.); (S.A.)
- Centro Sanitario, University of Calabria, 87036 Arcavacata di Rende (CS), Italy
- Correspondence: ; Tel.: +39-0984-496208
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Santoro M, De Amicis F, Aquila S, Bonofiglio D. Peroxisome proliferator-activated receptor gamma expression along the male genital system and its role in male fertility. Hum Reprod 2020; 35:2072-2085. [PMID: 32766764 DOI: 10.1093/humrep/deaa153] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 05/28/2020] [Indexed: 12/14/2022] Open
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) acts as a ligand activated transcription factor and regulates processes, such as energy homeostasis, cell proliferation and differentiation. PPARγ binds to DNA as a heterodimer with retinoid X receptor and it is activated by polyunsaturated fatty acids and fatty acid derivatives, such as prostaglandins. In addition, the insulin-sensitizing thiazolidinediones, such as rosiglitazone, are potent and specific activators of PPARγ. PPARγ is present along the hypothalamic-pituitary-testis axis and in the testis, where low levels in Leydig cells and higher levels in Sertoli cells as well as in germ cells have been found. High amounts of PPARγ were reported in the normal epididymis and in the prostate, but the receptor was almost undetectable in the seminal vesicles. Interestingly, in the human and in pig, PPARγ protein is highly expressed in ejaculated spermatozoa, suggesting a possible role of PPARγ signaling in the regulation of sperm biology. This implies that both natural and synthetic PPARγ ligands may act directly on sperm improving its performance. Given the close link between energy balance and reproduction, activation of PPARγ may have promising metabolic implications in male reproductive functions. In this review, we first describe PPARγ expression in different compartments of the male reproductive axis. Subsequently, we discuss the role of PPARγ in both physiological and several pathological conditions related to the male fertility.
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Affiliation(s)
- Marta Santoro
- Department of Pharmacy, Health and Nutritional Sciences (Department of Excellence, Italian Law 232/2016), Arcavacata di Rende, Cosenza 87036, Italy.,Centro Sanitario, University of Calabria, Arcavacata di Rende, Cosenza 87036, Italy
| | - Francesca De Amicis
- Department of Pharmacy, Health and Nutritional Sciences (Department of Excellence, Italian Law 232/2016), Arcavacata di Rende, Cosenza 87036, Italy
| | - Saveria Aquila
- Department of Pharmacy, Health and Nutritional Sciences (Department of Excellence, Italian Law 232/2016), Arcavacata di Rende, Cosenza 87036, Italy.,Centro Sanitario, University of Calabria, Arcavacata di Rende, Cosenza 87036, Italy
| | - Daniela Bonofiglio
- Department of Pharmacy, Health and Nutritional Sciences (Department of Excellence, Italian Law 232/2016), Arcavacata di Rende, Cosenza 87036, Italy.,Centro Sanitario, University of Calabria, Arcavacata di Rende, Cosenza 87036, Italy
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Stewart AN, MacLean SM, Stromberg AJ, Whelan JP, Bailey WM, Gensel JC, Wilson ME. Considerations for Studying Sex as a Biological Variable in Spinal Cord Injury. Front Neurol 2020; 11:802. [PMID: 32849242 PMCID: PMC7419700 DOI: 10.3389/fneur.2020.00802] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/26/2020] [Indexed: 12/13/2022] Open
Abstract
In response to NIH initiatives to investigate sex as a biological variable in preclinical animal studies, researchers have increased their focus on male and female differences in neurotrauma. Inclusion of both sexes when modeling neurotrauma is leading to the identification of novel areas for therapeutic and scientific exploitation. Here, we review the organizational and activational effects of sex hormones on recovery from injury and how these changes impact the long-term health of spinal cord injury (SCI) patients. When determining how sex affects SCI it remains imperative to expand outcomes beyond locomotor recovery and consider other complications plaguing the quality of life of patients with SCI. Interestingly, the SCI field predominately utilizes female rodents for basic science research which contrasts most other male-biased research fields. We discuss the unique caveats this creates to the translatability of preclinical research in the SCI field. We also review current clinical and preclinical data examining sex as biological variable in SCI. Further, we report how technical considerations such as housing, size, care management, and age, confound the interpretation of sex-specific effects in animal studies of SCI. We have uncovered novel findings regarding how age differentially affects mortality and injury-induced anemia in males and females after SCI, and further identified estrus cycle dysfunction in mice after injury. Emerging concepts underlying sexually dimorphic responses to therapy are also discussed. Through a combination of literature review and primary research observations we present a practical guide for considering and incorporating sex as biological variable in preclinical neurotrauma studies.
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Affiliation(s)
- Andrew N Stewart
- Department of Physiology, University of Kentucky, Lexington, KY, United States.,Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Steven M MacLean
- Department of Physiology, University of Kentucky, Lexington, KY, United States.,Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Arnold J Stromberg
- Department of Statistics, College of Arts and Sciences, University of Kentucky, Lexington, KY, United States
| | - Jessica P Whelan
- Department of Physiology, University of Kentucky, Lexington, KY, United States.,Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - William M Bailey
- Department of Physiology, University of Kentucky, Lexington, KY, United States.,Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - John C Gensel
- Department of Physiology, University of Kentucky, Lexington, KY, United States.,Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Melinda E Wilson
- Department of Physiology, University of Kentucky, Lexington, KY, United States
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Nuclear Receptors Are Differentially Expressed and Activated in KAIMRC1 Compared to MCF7 and MDA-MB231 Breast Cancer Cells. Molecules 2019; 24:molecules24112028. [PMID: 31141879 PMCID: PMC6600534 DOI: 10.3390/molecules24112028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 04/18/2019] [Accepted: 04/20/2019] [Indexed: 11/17/2022] Open
Abstract
We recently established a KAIMRC1 cell line that has unique features compared to the known breast cancer cell lines, MCF7 and MDA-MB231. To characterize it further, we investigated the expression profile of nuclear receptors and their respective co-factors in these cell lines. We confirm that in contrast to the triple negative cell line MDA-MB231, the MCF7 and KAIMRC1 are estrogen receptor alpha (ERa) and progesterone receptor alpha (PRa) positive, with significant lower expression of these receptors in KAIMRC1. KAIMRC1 cell is a vitamin D receptor (VDR) negative and V-ErbA-Related Protein 2 (EAR2) positive in contrast to MCF7 and MDA-MB231. Remarkably, the histone deacetylases (HDACs) are highly expressed in KAIRMC1 with HDAC6 and HDAC 7 are exclusively expressed in KAIMRC1 while thyroid hormone receptor-associated protein 80 (TRAP80), telomeric DNA binding protein 1 (TBP1) and TGF-beta receptor interacting protein (TRIP1) are absent in KAIMRC1 but present in MCF7 and MDA-MB231. In a luciferase reporter assay, the ERa coexpression is needed for estrogen receptor element (ERE)-luciferase activation by estradiol in KAIMRC1 but not in MCF7. The co-expression of exogenous Liver X receptor alpha (LXRa)/retinoid X receptor alpha (RXRa) are necessary for LXR responsive element (LXRE) activation by the GW3696 in the three cell lines. However, the activity of peroxisome proliferator-activated receptor response element (PPARE)-tk-luciferase reporter increased when peroxisome proliferator-activated receptors alpha (PPARa)/RXRa were coexpressed but the addition of PPARa agonist (GW7647) did not stimulate further the reporter. The signal of the PPARE reporter increased in a dose-dependent manner with rosiglitazone (PPARg agonist) in KAIMRC1, MCF7, and MDA-MB231 when the proliferator-activated receptors gamma (PPARg)/RXRa receptors were cotransfected. Retinoic acid-induced activation of retinoic acid receptor response element (RARE)-tk-luciferase is dependent on exogenous expression of retinoic acid receptor alpha (RARa)/RXRa heterodimer in MDA-MB 231 but not in MCF7 and KAIMRC1 cell lines. In the three cell lines, Bexarotene-induced retinoid X receptor response element (RXRE)-luciferase reporter activation was induced only if the RXRa/LXRa heterodimer were co-expressed. The vitamin D receptor response element (VDRE)-luciferase reporter activity showed another distinct feature of KAIMRC1, where only co-expression of exogenous vitamin D receptor (VDR)/RXRa heterodimer was sufficient to reach the maximum rate of activation of VDRE reporter. In the proliferation assay, nuclear receptors ligands showed a distinct effect on KAIMRC1 compared to MCF7 and MDA-MB231. Growth inhibition effects of used ligands suggest that KAIMRC1 correlate more closely to MDA-MB231 than MCF7. Vitamin D3, rosiglitazone, novel RXR compound (RXRc) and PPARa compound (GW6471) have the most profound effects. In conclusion, we showed that nuclear receptors are differentially expressed, activated and also their ligand produced distinct effects in KAIMRC1 compared to MCF7 and MDA-MB231. This finding gives us confidence that KAIMRC1 has a unique biological phenotype.
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Broekema M, Savage D, Monajemi H, Kalkhoven E. Gene-gene and gene-environment interactions in lipodystrophy: Lessons learned from natural PPARγ mutants. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:715-732. [PMID: 30742913 DOI: 10.1016/j.bbalip.2019.02.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 01/13/2019] [Accepted: 02/02/2019] [Indexed: 12/13/2022]
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Yan R, Wang Y, Shi M, Xiao Y, Liu L, Liu L, Guo B. Regulation of PTEN/AKT/FAK pathways by PPARγ impacts on fibrosis in diabetic nephropathy. J Cell Biochem 2019; 120:6998-7014. [PMID: 30652342 DOI: 10.1002/jcb.27937] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 10/02/2018] [Indexed: 02/06/2023]
Abstract
Renal tubular epithelial-to-mesenchymal transition (EMT) and tubulointerstitial fibrosis (TIF) are important pathological features of diabetic nephropathy (DN). However, the regulatory mechanism underlying EMT and TIF are still unclear. Previous studies showed that the decrease in the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was closely related to the aggravation of DN, but no published study showed how PTEN participated in the regulation of EMT and TIF. In this study, the rat proximal tubular epithelial cells (NRK52E) and C57BL mice and human kidney tissues were used as the research objects to investigate the mechanism underlying the regulatory effect of peroxisome proliferator-activated receptors γ (PPARγ) on PTEN and its influence on EMT and TIF, the regulation of PTEN's dual activity of lipid phosphatase/protein phosphatase by the serine threonine protein kinase B(AKT)/focal adhesion kinase (FAK) signaling pathway, and the role of PTEN in EMT and TIF. The results showed that PPARγ regulated the expression of PTEN at a transcriptional level and further regulated EMT and TIF. This dual activity could regulate the phosphorylation level of AKT and FAK and also affect FAK transcription. However, the 129 mutant of PTEN (PTEN-G129E) lost the lipid phosphatase activity, and its protein phosphatase activity was involved only in EMT and renal fibrosis through regulating FAK phosphorylation. This study systematically elucidated the role of PPARγ/PTEN/AKT/FAK signaling pathway in EMT and TIF during the pathogenesis of DN.
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Affiliation(s)
- Rui Yan
- Department of Nephrology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yuanyuan Wang
- Department of Pathophysiology, Guizhou Medical University, Guiyang, China
| | - Mingjun Shi
- Department of Pathophysiology, Guizhou Medical University, Guiyang, China
| | - Ying Xiao
- Department of Pathophysiology, Guizhou Medical University, Guiyang, China
| | - Lirong Liu
- Department of Clinical Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Lingling Liu
- Department of Pathophysiology, Guizhou Medical University, Guiyang, China
| | - Bing Guo
- Department of Pathophysiology, Guizhou Medical University, Guiyang, China
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Orkhon B, Kobayashi K, Javzan B, Sasaki K. Astragalus root induces ovarian β‑oxidation and suppresses estrogen‑dependent uterine proliferation. Mol Med Rep 2018; 18:5198-5206. [PMID: 30272268 DOI: 10.3892/mmr.2018.9493] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 03/26/2018] [Indexed: 11/06/2022] Open
Abstract
Continuous estrogen stimulation in the uterus has been known to cause excess proliferation of the functional layer of endometrium, resulting in endometrial hyperplasia and leading to infertility. Estrogens can modulate other nuclear receptor signaling pathways, such as peroxisome proliferator‑activated receptors (PPARs). Astragalus root (AsR) has exhibited strong PPARα agonistic activity. Female Imprinting Control Region mice were fed a powder diet that included 5% AsR hot water extract or 0.1% bezafibrate as a positive control for 56 days to investigate AsR effects on the reproductive tract, ovary and uterus. AsR resulted in upregulation of the expression of uterine and ovarian PPARα mRNA by 2.5‑fold, and 1.5‑fold, respectively, compared with controls. AsR significantly increased ovarian expression levels of mitochondrial 2,4‑dienoyl‑CoA reductase (mDECR), an auxiliary enzyme involved in β‑oxidation. AsR‑fed mice also exhibited a significant increase in blood estradiol levels and tended to have higher ovary weight. AsR resulted in significantly decreased uterine weight and mDECR expression levels. It has been reported that a PPARα agonist suppresses the development of estrogen‑dependent endometrial hyperplasia. These findings raise the possibility that AsR suppresses estrogen‑dependent endometrial hyperplasia and ovarian dysfunction leading to infertility.
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Affiliation(s)
- Banzragchgarav Orkhon
- Department of Pharmacognosy, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi 981‑8558, Japan
| | - Kyoko Kobayashi
- Department of Pharmacognosy, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi 981‑8558, Japan
| | - Batkhuu Javzan
- School of Engineering and Applied Sciences, National University of Mongolia, Ulaanbaatar 14201, Mongolia
| | - Kenroh Sasaki
- Department of Pharmacognosy, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi 981‑8558, Japan
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Fan P, Abderrahman B, Chai TS, Yerrum S, Jordan VC. Targeting Peroxisome Proliferator-Activated Receptor γ to Increase Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells. Mol Cancer Ther 2018; 17:2732-2745. [PMID: 30224430 DOI: 10.1158/1535-7163.mct-18-0088] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 06/07/2018] [Accepted: 09/10/2018] [Indexed: 12/25/2022]
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is an important transcription factor that modulates lipid metabolism and inflammation. However, it remains unclear whether PPARγ is involved in modulation of estrogen (E2)-induced inflammation, thus affecting apoptosis of E2-deprived breast cancer cells, MCF-7:5C and MCF-7:2A. Here, we demonstrated that E2 treatment suppressed the function of PPARγ in both cell lines, although the suppressive effect in MCF-7:2A cells was delayed owing to high PPARγ expression. Activation of PPARγ by a specific agonist, pioglitazone, selectively blocked the induction of TNFα expression by E2, but did not affect other adipose inflammatory genes, such as fatty acid desaturase 1 and IL6. This suppression of TNFα expression by pioglitazone was mainly mediated by transrepression of nuclear factor-κB (NF-κB) DNA-binding activity. A novel finding was that NF-κB functions as an oxidative stress inducer in MCF-7:5C cells but an antioxidant in MCF-7:2A cells. Therefore, the NF-κB inhibitor JSH-23 displayed effects equivalent to those of pioglitazone, with complete inhibition of apoptosis in MCF-7:5C cells, but it increased E2-induced apoptosis in MCF-7:2A cells. Depletion of PPARγ by siRNA or the PPARγ antagonist T0070907 accelerated E2-induced apoptosis, with activation of NF-κB-dependent TNFα and oxidative stress. For the first time, we demonstrated that PPARγ is a growth signal and has potential to modulate NF-κB activity and oxidative stress in E2-deprived breast cancer cell lines. All of these findings suggest that anti-PPARγ therapy is a novel strategy to improve the therapeutic effects of E2-induced apoptosis in E2-deprived breast cancer.
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Affiliation(s)
- Ping Fan
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Balkees Abderrahman
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tina S Chai
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,University of Virginia, Charlottesville, Virginia
| | - Smitha Yerrum
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - V Craig Jordan
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Kühn G, Pallauf K, Schulz C, Rimbach G. Flavonoids as putative modulators of Δ4-, Δ5-, and Δ6-desaturases: Studies in cultured hepatocytes, myocytes, and adipocytes. Biofactors 2018; 44:485-495. [PMID: 30365230 DOI: 10.1002/biof.1443] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 06/07/2018] [Accepted: 06/27/2018] [Indexed: 12/19/2022]
Abstract
This study was conducted to screen flavonoids for affecting expression of desaturases involved in omega-3 fatty acid synthesis and ceramide (CER) metabolism. To this end, cultured HepG2 hepatocytes, C2C12 myocytes, and 3T3-L1 adipocytes were treated with nontoxic concentrations of 12 selected flavonoids and expression of Δ4-, Δ5-, and Δ6-desaturases (DEGS1, FADS1, and FADS2, respectively) was determined. The flavonoids tested were more cytotoxic to HepG2 and 3T3-L1 than to C2C12 cells. In HepG2 cells, FADS1 was induced by quercetin and FADS2 expression was increased by daidzein, genistein, and pratensein treatment. DEGS1 was increased by apigenin, luteolin, orobol, and quercetin administration. In differentiated C2C12 cells, substances had no inducing effect or even lowered target gene expression. Pratensein induced both FADS1 and FADS2 in differentiated 3T3-L1 cells and DEGS1 was increased by treatment with apigenin, genistein, luteolin, orobol, and quercetin. In conclusion, pratensein may be an interesting test compound for further studies in vitro and in vivo on omega-3 synthesis since it induces its rate-limiting enzyme FADS2. Apigenin, luteolin, orobol, and quercetin induced DEGS1 and thereby possibly synthesis of proapoptotic CER in malignant HepG2 cells and 3T3-L1. In contrast, in benign C2C12 cells, they did not elevate mRNA steady state levels of DEGS1. That may partly explain the higher resistance of C2C12 cells against flavonoids compared to the other cell lines. By affecting tumor cells and nontumor cells differently, these flavonoids may be promising substances for further research regarding anticancer properties. © 2018 BioFactors, 44(5):485-495, 2018.
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Affiliation(s)
- Gianna Kühn
- Institute of Human Nutrition and Food Science, University of Kiel, Kiel, Germany
| | - Kathrin Pallauf
- Institute of Human Nutrition and Food Science, University of Kiel, Kiel, Germany
| | - Carsten Schulz
- Institute of Animal Breeding and Husbandry, University of Kiel, Kiel, Germany
- GMA-Gesellschaft für Marine Aquakultur mbH, Büsum, Germany
| | - Gerald Rimbach
- Institute of Human Nutrition and Food Science, University of Kiel, Kiel, Germany
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Bisphenol A and its derivatives decrease expression of chemerin, which reverses its stimulatory action in ovarian cancer cells. Toxicol Lett 2018; 291:61-69. [PMID: 29653259 DOI: 10.1016/j.toxlet.2018.04.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 03/09/2018] [Accepted: 04/09/2018] [Indexed: 12/14/2022]
Abstract
Chemerin is an adipocyte-secreted protein that associates with obesity, inflammation, metabolic dysfunction, and carcinogenesis. Previous studies have shown human granulosa cells to produce bioactive chemerin and its receptor CMKLR1. In the present study, we demonstrated that the mRNA level of chemerin receptor is higher in a granulosa cell tumor cell line than in epithelial cancer cells, whereas chemerin expression and secretion were lower. Various exogenous factors, such as bisphenol A and its halogenated derivatives tetrabromobisphenol A and tetrachlorobisphenol A, can affect adipokine expression. For this reason, we investigated the effects of bisphenol A and its derivatives on the expression of chemerin and its receptor. At low nanomolar concentrations, BPA, TBBPA, and TCBPA decreased chemerin expression and secretion only in granulosa cell tumor COV434 cells by both peroxisome proliferator-activated receptor γ and estrogen receptor signaling pathways. Chemerin treatment had no effect on proliferation of ovarian non-cancer and cancer cell lines. However, we also found evidence to support the inhibition of BPA- and TBBPA-induced cell proliferation by chemerin. Taken together, our results indicate for the first time that BPA and its derivatives down-regulate chemerin expression, which can suppress the ability of BPA to induce proliferation. Moreover, both PPARγ and ERs were involved in the BPA-induced decrease in chemerin expression, and its ratio was crucial to exert these effects.
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40
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Rovito D, Gionfriddo G, Barone I, Giordano C, Grande F, De Amicis F, Lanzino M, Catalano S, Andò S, Bonofiglio D. Ligand-activated PPARγ downregulates CXCR4 gene expression through a novel identified PPAR response element and inhibits breast cancer progression. Oncotarget 2018; 7:65109-65124. [PMID: 27556298 PMCID: PMC5323141 DOI: 10.18632/oncotarget.11371] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 08/11/2016] [Indexed: 12/26/2022] Open
Abstract
Stromal Derived Factor-1α (SDF-1α) and its cognate receptor CXCR4 play a key role in mediating breast cancer cell invasion and metastasis. Therefore, drugs able to inhibit CXCR4 activation may add critical tools to reduce tumor progression, especially in the most aggressive form of the breast cancer disease. Peroxisome Proliferator-Activated Receptor (PPAR) γ, a member of the nuclear receptor superfamily, has been found to downregulate CXCR4 gene expression in different cancer cells, however the molecular mechanism underlying this effect is not fully understood. Here, we identified a novel PPARγ-mediated mechanism that negatively regulates CXCR4 expression in both epithelial and stromal breast cancer cells. We found that ligand-activated PPARγ downregulated CXCR4 transcriptional activity through the recruitment of the silencing mediator of retinoid and thyroid hormone receptor (SMRT) corepressor onto a newly identified PPAR response element (PPRE) within the CXCR4 promoter in breast cancer cell lines. As a consequence, the PPARγ agonist rosiglitazone (BRL) significantly inhibited cell migration and invasion and this effect was PPARγ-mediated, since it was reversed in the presence of the PPARγ antagonist GW9662. According to the ability of cancer-associated fibroblasts (CAFs), the most abundant component of breast cancer stroma, to secrete high levels of SDF-1α, BRL reduced migratory promoting activities induced by conditioned media (CM) derived from CAFs and affected CXCR4 downstream signaling pathways activated by CAF-CM. In addition, CAFs exposed to BRL showed a decreased expression of CXCR4, a reduced motility and invasion along with a phenotype characterized by an altered morphology. Collectively, our findings provide novel insights into the role of PPARγ in inhibiting breast cancer progression and further highlight the utility of PPARγ ligands for future therapies aimed at targeting both cancer and surrounding stromal cells in breast cancer patients.
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Affiliation(s)
- Daniela Rovito
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.,Centro Sanitario, University of Calabria, Rende (CS), Italy
| | - Giulia Gionfriddo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Ines Barone
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | | | - Fedora Grande
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Francesca De Amicis
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Marilena Lanzino
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.,Centro Sanitario, University of Calabria, Rende (CS), Italy
| | - Daniela Bonofiglio
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
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Haddadi N, Lin Y, Travis G, Simpson AM, McGowan EM, Nassif NT. PTEN/PTENP1: 'Regulating the regulator of RTK-dependent PI3K/Akt signalling', new targets for cancer therapy. Mol Cancer 2018; 17:37. [PMID: 29455665 PMCID: PMC5817727 DOI: 10.1186/s12943-018-0803-3] [Citation(s) in RCA: 196] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 02/01/2018] [Indexed: 12/14/2022] Open
Abstract
Regulation of the PI-3 kinase (PI3K)/Akt signalling pathway is essential for maintaining the integrity of fundamental cellular processes, cell growth, survival, death and metabolism, and dysregulation of this pathway is implicated in the development and progression of cancers. Receptor tyrosine kinases (RTKs) are major upstream regulators of PI3K/Akt signalling. The phosphatase and tensin homologue (PTEN), a well characterised tumour suppressor, is a prime antagonist of PI3K and therefore a negative regulator of this pathway. Loss or inactivation of PTEN, which occurs in many tumour types, leads to overactivation of RTK/PI3K/Akt signalling driving tumourigenesis. Cellular PTEN levels are tightly regulated by a number of transcriptional, post-transcriptional and post-translational regulatory mechanisms. Of particular interest, transcription of the PTEN pseudogene, PTENP1, produces sense and antisense transcripts that exhibit post-transcriptional and transcriptional modulation of PTEN expression respectively. These additional levels of regulatory complexity governing PTEN expression add to the overall intricacies of the regulation of RTK/PI-3 K/Akt signalling. This review will discuss the regulation of oncogenic PI3K signalling by PTEN (the regulator) with a focus on the modulatory effects of the sense and antisense transcripts of PTENP1 on PTEN expression, and will further explore the potential for new therapeutic opportunities in cancer treatment.
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Affiliation(s)
- Nahal Haddadi
- School of Life Sciences, Faculty of Science, University of Technology Sydney, 15 Broadway, Ultimo, Sydney, NSW 2007 Australia
| | - Yiguang Lin
- School of Life Sciences, Faculty of Science, University of Technology Sydney, 15 Broadway, Ultimo, Sydney, NSW 2007 Australia
| | - Glena Travis
- School of Life Sciences, Faculty of Science, University of Technology Sydney, 15 Broadway, Ultimo, Sydney, NSW 2007 Australia
| | - Ann M. Simpson
- School of Life Sciences, Faculty of Science, University of Technology Sydney, 15 Broadway, Ultimo, Sydney, NSW 2007 Australia
| | - Eileen M. McGowan
- School of Life Sciences, Faculty of Science, University of Technology Sydney, 15 Broadway, Ultimo, Sydney, NSW 2007 Australia
- Central Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080 China
| | - Najah T. Nassif
- School of Life Sciences, Faculty of Science, University of Technology Sydney, 15 Broadway, Ultimo, Sydney, NSW 2007 Australia
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42
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Rzemieniec J, Litwa E, Wnuk A, Lason W, Kajta M. Bazedoxifene and raloxifene protect neocortical neurons undergoing hypoxia via targeting ERα and PPAR-γ. Mol Cell Endocrinol 2018; 461:64-78. [PMID: 28859903 DOI: 10.1016/j.mce.2017.08.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 07/04/2017] [Accepted: 08/28/2017] [Indexed: 12/12/2022]
Abstract
Selective estrogen receptor modulators (SERMs) such as bazedoxifene and raloxifene are recognized to mainly act via estrogen receptors (ERs), but there is no study examining the involvement of PPAR-γ in their actions, especially in neurons undergoing hypoxia. Little is also known about age-dependent actions of the SERMs on neuronal tissue challenged with hypoxia. In this study, bazedoxifene and raloxifene protected neocortical cells against hypoxia at early and later developmental stages. Both SERMs evoked caspase-3-independent neuroprotection and increased protein levels of ERα (66 and 46 kDa isoforms) and PPAR-γ. In addition, bazedoxifene enhanced expression of ERα-regulated Cyp19a1 mRNA. Using double siRNA silencing, for the first time we demonstrated a key role of ERα and PPAR-γ in the neuroprotective action of the SERMs in neocortical neurons undergoing hypoxia. This study provides prospects for the development of a new therapeutic strategies against hypoxic brain injury that selectively target ERα and/or PPAR-γ.
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Affiliation(s)
- J Rzemieniec
- Institute of Pharmacology, Polish Academy of Sciences, Department of Experimental Neuroendocrinology, 31-343 Krakow, Smetna Street 12, Poland
| | - E Litwa
- Institute of Pharmacology, Polish Academy of Sciences, Department of Experimental Neuroendocrinology, 31-343 Krakow, Smetna Street 12, Poland
| | - A Wnuk
- Institute of Pharmacology, Polish Academy of Sciences, Department of Experimental Neuroendocrinology, 31-343 Krakow, Smetna Street 12, Poland
| | - W Lason
- Institute of Pharmacology, Polish Academy of Sciences, Department of Experimental Neuroendocrinology, 31-343 Krakow, Smetna Street 12, Poland
| | - M Kajta
- Institute of Pharmacology, Polish Academy of Sciences, Department of Experimental Neuroendocrinology, 31-343 Krakow, Smetna Street 12, Poland.
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43
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Du R, Lin L, Cheng D, Xu Y, Xu M, Chen Y, Wang W, Bi Y, Li D, Lu J. Thiazolidinedione therapy and breast cancer risk in diabetic women: A systematic review and meta-analysis. Diabetes Metab Res Rev 2018; 34. [PMID: 29125710 DOI: 10.1002/dmrr.2961] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Revised: 10/06/2017] [Accepted: 11/01/2017] [Indexed: 01/02/2023]
Abstract
Rising experimental evidence suggests that thiazolidinediones (TZDs) exert a protective effect on breast cancer. However, studies concerning this issue were inconsistent and limited. Hence, we performed a meta-analysis with data from currently available studies to evaluate the effect of TZDs on breast cancer risk among diabetic women. We comprehensively searched for all pertinent studies addressing TZDs use and breast cancer risk published before January 1, 2016, in PubMed, Clinical Trials, and Cochrane Library. Data synthesis was performed in a random-effects model using Stata version 12.0 (Stata Corp, College Station, Texas). Fourteen independent studies were eventually selected in this meta-analysis, including 5 randomized controlled clinical trials (RCTs), 7 cohort studies, and 2 case-control studies. No significant associations of TZD use and risk of breast cancer were observed in the RCTs (pooled risk ratio [RR]: 0.77, 95% confidence interval (CI), 0.39-1.53, I2 = 26%) or case-control studies (pooled odds ratio, 0.99, 95% CI, 0.76-1.28, I2 = 31%). A 19% reduction in breast cancer risk (pooled RR: 0.81, 95% CI, 0.66-0.99, I2 = 72%) was found in the cohort studies. However, after removing the study with the smallest event number and the greatest effect size, the association became nonsignificant with greatly decreased heterogeneity (pooled RR: 0.94, 95% CI, 0.86-1.03, I2 = 16%). This meta-analysis did not find any significant association between TZDs use and risk of breast cancer among diabetic women.
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Affiliation(s)
- Rui Du
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Lin
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Di Cheng
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Xu
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Xu
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuhong Chen
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiqing Wang
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yufang Bi
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jieli Lu
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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44
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Kim DH, Suh J, Surh YJ, Na HK. Regulation of the tumor suppressor PTEN by natural anticancer compounds. Ann N Y Acad Sci 2017; 1401:136-149. [PMID: 28891094 DOI: 10.1111/nyas.13422] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 05/31/2017] [Accepted: 06/05/2017] [Indexed: 12/20/2022]
Abstract
The tumor suppressor phosphatase and tensin homologue (PTEN) has phosphatase activity, with phosphatidylinositol (3,4,5)-trisphosphate (PIP3), a product of phosphatidylinositol 3-kinase (PI3K), as one of the principal substrates. PTEN is a negative regulator of the Akt pathway, which plays a fundamental role in controlling cell growth, survival, and proliferation. Loss of PTEN function has been observed in many different types of cancer. Functional inactivation of PTEN as a consequence of germ-line mutations or promoter hypermethylation predisposes individuals to malignancies. PTEN undergoes posttranslational modifications, such as oxidation, acetylation, phosphorylation, SUMOylation, and ubiquitination, which influence its catalytic activity, interactions with other proteins, and subcellular localization. Cellular redox status is crucial for posttranslational modification of PTEN and its functional consequences. Oxidative stress and inflammation are major causes of loss of PTEN function. Pharmacologic or nutritional restoration of PTEN function is considered a reliable strategy in the management of PTEN-defective cancer. In this review, we highlight natural compounds, such as curcumin, indol-3 carbinol, and omega-3 fatty acids, that have the potential to restore or potentiate PTEN expression/activity, thereby suppressing cancer cell proliferation, survival, and resistance to chemotherapeutic agents.
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Affiliation(s)
- Do-Hee Kim
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Jinyoung Suh
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University, Seoul, South Korea.,Cancer Research Institute, Seoul National University, Seoul, South Korea
| | - Hye-Kyung Na
- Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering, Sungshin Women's University, Seoul, South Korea
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45
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Wang Y, Ung MH, Xia T, Cheng W, Cheng C. Cancer cell line specific co-factors modulate the FOXM1 cistrome. Oncotarget 2017; 8:76498-76515. [PMID: 29100329 PMCID: PMC5652723 DOI: 10.18632/oncotarget.20405] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 08/14/2017] [Indexed: 12/11/2022] Open
Abstract
ChIP-seq has been commonly applied to identify genomic occupation of transcription factors (TFs) in a context-specific manner. It is generally assumed that a TF should have similar binding patterns in cells from the same or closely related tissues. Surprisingly, this assumption has not been carefully examined. To this end, we systematically compared the genomic binding of the cell cycle regulator FOXM1 in eight cell lines from seven different human tissues at binding signal, peaks and target genes levels. We found that FOXM1 binding in ER-positive breast cancer cell line MCF-7 are distinct comparing to those in not only other non-breast cell lines, but also MDA-MB-231, ER-negative breast cancer cell line. However, binding sites in MDA-MB-231 and non-breast cell lines were highly consistent. The recruitment of estrogen receptor alpha (ERα) caused the unique FOXM1 binding patterns in MCF-7. Moreover, the activity of FOXM1 in MCF-7 reflects the regulatory functions of ERα, while in MDA-MB-231 and non-breast cell lines, FOXM1 activities regulate cell proliferation. Our results suggest that tissue similarity, in some specific contexts, does not hold precedence over TF-cofactors interactions in determining transcriptional states and that the genomic binding of a TF can be dramatically affected by a particular co-factor under certain conditions.
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Affiliation(s)
- Yue Wang
- School of Electronic Information and Communications, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.,Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Matthew H Ung
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Tian Xia
- School of Electronic Information and Communications, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Wenqing Cheng
- School of Electronic Information and Communications, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Chao Cheng
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.,Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03766, USA.,Department of Biomedical Data Sciences, Geisel School of Medicine at Dartmouth, Lebanon, NH 03766, USA
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46
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Chen L, Yuan Y, Kar S, Kanchi MM, Arora S, Kim JE, Koh PF, Yousef E, Samy RP, Shanmugam MK, Tan TZ, Shin SW, Arfuso F, Shen HM, Yang H, Goh BC, Park JI, Gaboury L, Lobie PE, Sethi G, Lim LHK, Kumar AP. PPARγ Ligand-induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers. Mol Cancer Ther 2017; 16:2528-2542. [PMID: 29021293 DOI: 10.1158/1535-7163.mct-16-0739] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 05/17/2017] [Accepted: 07/20/2017] [Indexed: 11/16/2022]
Abstract
Metastatic breast cancer is still incurable so far; new specifically targeted and more effective therapies for triple-negative breast cancer (TNBC) are required in the clinic. In this study, our clinical data have established that basal and claudin-low subtypes of breast cancer (TNBC types) express significantly higher levels of Annexin A1 (ANXA1) with poor survival outcomes. Using human cancer cell lines that model the TNBC subtype, we observed a strong positive correlation between expression of ANXA1 and PPARγ. A similar correlation between these two markers was also established in our clinical breast cancer patients' specimens. To establish a link between these two markers in TNBC, we show de novo expression of ANXA1 is induced by activation of PPARγ both in vitro and in vivo and it has a predictive value in determining chemosensitivity to PPARγ ligands. Mechanistically, we show for the first time PPARγ-induced ANXA1 protein directly interacts with receptor interacting protein-1 (RIP1), promoting its deubiquitination and thereby activating the caspase-8-dependent death pathway. We further identified this underlying mechanism also involved a PPARγ-induced ANXA1-dependent autoubiquitination of cIAP1, the direct E3 ligase of RIP1, shifting cIAP1 toward proteosomal degradation. Collectively, our study provides first insight for the suitability of using drug-induced expression of ANXA1 as a new player in RIP1-induced death machinery in TNBCs, presenting itself both as an inclusion criterion for patient selection and surrogate marker for drug response in future PPARγ chemotherapy trials. Mol Cancer Ther; 16(11); 2528-42. ©2017 AACR.
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Affiliation(s)
- Luxi Chen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore.,Department of Pharmacology, National University of Singapore, Singapore.,Department of Chemistry and Biochemistry, School of Natural Sciences & Mathematics, The University of Texas at Dallas, Texas
| | - Yi Yuan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Shreya Kar
- Cancer Science Institute of Singapore, National University of Singapore, Singapore.,Department of Pharmacology, National University of Singapore, Singapore
| | - Madhu M Kanchi
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Suruchi Arora
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ji E Kim
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Pei F Koh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore.,Department of Pharmacology, National University of Singapore, Singapore
| | - Einas Yousef
- Institute for Research in Immunology and Cancer, Universite de Montreal, Montreal, Quebec, Canada.,Department of Histology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Ramar P Samy
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Muthu K Shanmugam
- Department of Pharmacology, National University of Singapore, Singapore
| | - Tuan Z Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Sung W Shin
- Department of Biochemistry, Dong-A University, College of Medicine, Busan, South Korea
| | - Frank Arfuso
- Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA, Australia
| | - Han M Shen
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
| | - Henry Yang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Boon C Goh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore.,Department of Pharmacology, National University of Singapore, Singapore.,Department of Haematology-Oncology, National University Health System, Singapore.,National University Cancer Institute, National University Health System, Singapore
| | - Joo I Park
- Department of Biochemistry, Dong-A University, College of Medicine, Busan, South Korea
| | - Louis Gaboury
- Institute for Research in Immunology and Cancer, Universite de Montreal, Montreal, Quebec, Canada
| | - Peter E Lobie
- Cancer Science Institute of Singapore, National University of Singapore, Singapore.,Department of Pharmacology, National University of Singapore, Singapore.,National University Cancer Institute, National University Health System, Singapore.,Tsinghua Berkeley Shenzhen Institute and Division of Life Science and Health, Tsinghua University Graduate School, Shenzhen, P.R. China
| | - Gautam Sethi
- Department of Pharmacology, National University of Singapore, Singapore.,School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA, Australia
| | - Lina H K Lim
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. .,NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.,NUS Immunology Program, National University of Singapore, Singapore
| | - Alan P Kumar
- Cancer Science Institute of Singapore, National University of Singapore, Singapore. .,Department of Pharmacology, National University of Singapore, Singapore.,National University Cancer Institute, National University Health System, Singapore.,Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth WA, Australia.,Department of Biological Sciences, University of North Texas, Denton, Texas
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47
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PPARs as determinants of the estrogen receptor lineage: use of synthetic lethality for the treatment of estrogen receptor-negative breast cancer. Oncotarget 2017; 8:50337-50341. [PMID: 28881566 PMCID: PMC5584135 DOI: 10.18632/oncotarget.17302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 03/02/2017] [Indexed: 11/26/2022] Open
Abstract
The Dilemma Estrogen receptora-negative (ER-) breast cancer lacks a specific critical target to control tumor progression. The Objective To identify mechanisms that enable increased expression of the ER+ lineage in an otherwise ER- breast cancer. Preface The nuclear receptor superfamily members PPARγ and PPARδ regulate gene expression associated with a multitude of pathways, including intermediary metabolism, angiogenesis, proliferation and inflammation (see reviews [1–3]). Recent developments using transgenic and knockout mice, as well as pharmacologic intervention with PPARγ and PPARδ agonists, have revealed a previously unknown relationship between PPARγ suppression and PPARδ activation that leads to the appearance of ER+ tumors, enabling a synthetic lethality approach by anti-ER therapy. The ability to selectively affect the ER+ lineage by modulating PPARγ and PPARδ activity represents a new clinical paradigm and opportunity to treat ER- cancer with PPARγ and PPARδ modulating agents, ultimately rendering them more responsive to adjuvant therapy.
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Mediating Roles of PPARs in the Effects of Environmental Chemicals on Sex Steroids. PPAR Res 2017; 2017:3203161. [PMID: 28819354 PMCID: PMC5551527 DOI: 10.1155/2017/3203161] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 05/23/2017] [Accepted: 06/21/2017] [Indexed: 12/18/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that are widely involved in various physiological functions. They are widely expressed through the reproductive system. Their roles in the metabolism and function of sex steroids and thus the etiology of reproductive disorders receive great concern. Various kinds of exogenous chemicals, especially environmental pollutants, exert their adverse impact on the reproductive system through disturbing the PPAR signaling pathway. Chemicals could bind to PPARs and modulate the transcription of downstream genes containing PPRE (peroxisome proliferator response element). This will lead to altered expression of genes related to metabolism of sex steroids and thus the abnormal physiological function of sex steroids. In this review, various kinds of environmental ligands are summarized and discussed. Their interactions with three types of PPARs are classified by various data from transcript profiles, PPRE reporter in cell line, in silico docking, and gene silencing. The review will contribute to the understanding of the roles of PPARs in the reproductive toxicology of environmental chemicals.
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Lu Q, Schnitzler GR, Vallaster CS, Ueda K, Erdkamp S, Briggs CE, Iyer LK, Jaffe IZ, Karas RH. Unliganded estrogen receptor alpha regulates vascular cell function and gene expression. Mol Cell Endocrinol 2017; 442:12-23. [PMID: 27888004 DOI: 10.1016/j.mce.2016.11.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 11/03/2016] [Accepted: 11/21/2016] [Indexed: 01/15/2023]
Abstract
The unliganded form of the estrogen receptor is generally thought to be inactive. Our prior studies, however, suggested that unliganded estrogen receptor alpha (ERα) exacerbates adverse vascular injury responses in mice. Here, we show that the presence of unliganded ERα decreases vascular endothelial cell (EC) migration and proliferation, increases smooth muscle cell (SMC) proliferation, and increases inflammatory responses in cultured ECs and SMCs. Unliganded ERα also regulates many genes in vascular ECs and mouse aorta. Activation of ERα by E2 reverses the cell physiological effects of unliganded ERα, and promotes gene regulatory effects that are predicted to counter the effects of unliganded ERα. These results reveal that the unliganded form of ERα is not inert, but significantly impacts gene expression and physiology of vascular cells. Furthermore, they indicate that the cardiovascular protective effects of estrogen may be connected to its ability to counteract these effects of unliganded ERα.
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Affiliation(s)
- Qing Lu
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
| | - Gavin R Schnitzler
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
| | - Caroline S Vallaster
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
| | - Kazutaka Ueda
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
| | - Stephanie Erdkamp
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
| | - Christine E Briggs
- Tufts Center for Neuroscience Research, Neuroscience Department, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Lakshmanan K Iyer
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
| | - Iris Z Jaffe
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
| | - Richard H Karas
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
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Lopes C, Madureira TV, Ferreira N, Pinheiro I, Castro LFC, Rocha E. Peroxisome proliferator-activated receptor gamma (PPARγ) in brown trout: Interference of estrogenic and androgenic inputs in primary hepatocytes. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2016; 46:328-336. [PMID: 27541269 DOI: 10.1016/j.etap.2016.08.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 08/05/2016] [Accepted: 08/08/2016] [Indexed: 06/06/2023]
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a pivotal regulator of lipid and glucose metabolism in vertebrates. Here, we isolated and characterized for the first time the PPARγ gene from brown trout (Salmo trutta f. fario). Hormones have been reported to interfere with the regulatory function of PPARγ in various organisms, albeit with little focus on fish. Thus, primary hepatocytes isolated from juveniles of brown trout were exposed to 1, 10 and 50μM of ethinylestradiol (EE2) or testosterone (T). A significant (3 fold) decrease was obtained in response to 50μM of EE2 and to 10 and 50μM of T (13 and 14 folds), while a 3 fold increase was observed at 1μM of EE2. Therefore, trout PPARγ seems a target for natural/synthetic compounds with estrogenic or androgenic properties and so, we advocate considering PPARγ as another alert sensor gene when assessing the effects of sex-steroid endocrine disruptors.
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Affiliation(s)
- Célia Lopes
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), U.Porto - University of Porto, Rua dos Bragas 289, P 4050-123 Porto, Portugal; Institute of Biomedical Sciences Abel Salazar (ICBAS), U.Porto - University of Porto, Laboratory of Histology and Embryology, Department of Microscopy, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto, Portugal
| | - Tânia Vieira Madureira
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), U.Porto - University of Porto, Rua dos Bragas 289, P 4050-123 Porto, Portugal; Institute of Biomedical Sciences Abel Salazar (ICBAS), U.Porto - University of Porto, Laboratory of Histology and Embryology, Department of Microscopy, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto, Portugal.
| | - Nádia Ferreira
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), U.Porto - University of Porto, Rua dos Bragas 289, P 4050-123 Porto, Portugal; Institute of Biomedical Sciences Abel Salazar (ICBAS), U.Porto - University of Porto, Laboratory of Histology and Embryology, Department of Microscopy, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto, Portugal
| | - Ivone Pinheiro
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), U.Porto - University of Porto, Rua dos Bragas 289, P 4050-123 Porto, Portugal; Institute of Biomedical Sciences Abel Salazar (ICBAS), U.Porto - University of Porto, Laboratory of Histology and Embryology, Department of Microscopy, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto, Portugal
| | - L Filipe C Castro
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), U.Porto - University of Porto, Rua dos Bragas 289, P 4050-123 Porto, Portugal; Faculty of Sciences (FCUP), U.Porto - University of Porto, Department of Biology, Rua do Campo Alegre, P 4169-007 Porto, Portugal
| | - Eduardo Rocha
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), U.Porto - University of Porto, Rua dos Bragas 289, P 4050-123 Porto, Portugal; Institute of Biomedical Sciences Abel Salazar (ICBAS), U.Porto - University of Porto, Laboratory of Histology and Embryology, Department of Microscopy, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto, Portugal
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