|
1
|
Yang Y, Brenna A, Potenza DM, Sundaramoorthy S, Cheng X, Ming XF, Yang Z. Arginase-II promotes melanoma and lung cancer cell growth by regulating Sirt3-mtROS axis. Front Cell Dev Biol 2025; 13:1528972. [PMID: 40177131 PMCID: PMC11961885 DOI: 10.3389/fcell.2025.1528972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 02/27/2025] [Indexed: 04/05/2025] Open
Abstract
Background Aberrant mitochondrial metabolism is a key source of massive mitochondrial reactive oxygen species (mtROS) in tumour cells. Arginase-II (Arg-II), a widely expressed mitochondrial metabolic enzyme, has recently been shown to enhance mtROS production and melanoma progression. However, how Arg-II enhances mtROS and whether mtROS is involved in stimulation of cancer cell proliferation and migration remain unclear. Methods and results Here, we show that ablation of arg-ii suppresses cell growth, migration, nuclear deformation, and DNA damage in melanoma cells. Vice versa, overexpression of arg-ii in melanoma cells promotes melanoma cell growth and migration accompanied by enhanced nuclear deformation and DNA damage. Ablation or overexpression of arg-ii reduces or enhances mtROS, respectively, accounting for the effects of Arg-II on melanoma growth, migration, and DNA damage. Further data demonstrate that Arg-II enhances mtROS through decreasing Sirtuin 3 (Sirt3) levels. Silencing sirt3 promotes melanoma growth, migration, nuclear deformation, and DNA damage through enhancing mtROS. In supporting of these findings, overexpression of sirt3 prevented Arg-II-induced mtROS production with concomitant prevention of Arg-II-induced cell growth, migration, nuclear deformation and DNA damage. Furthermore, we show that upregulation of Arg-II under hypoxia induces nuclear deformation and DNA damage through suppressing Sirt3. Similar results are obtained in A549 human lung carcinoma cells. In addition, analysis of publicly accessible datasets reveals that elevated arg-ii mRNA levels in human tumor samples including skin cutaneous melanoma and lung cancers associate with poorer prognosis. Conclusion Altogether, our findings demonstrate a critical role of Arg-II-Sirt3-mtROS cascade in promoting melanoma growth, migration, nuclear deformation, and DNA damage linking to melanoma progression and malignancy, which could be therapeutic targets for cancers such as melanoma and lung carcinoma.
Collapse
|
|
2
|
Tharayil JS, Kandettu A, Chakrabarty S. The curious case of mitochondrial sirtuin in rewiring breast cancer metabolism: Mr Hyde or Dr Jekyll? Biochim Biophys Acta Mol Basis Dis 2025; 1871:167691. [PMID: 39864670 DOI: 10.1016/j.bbadis.2025.167691] [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: 08/17/2024] [Revised: 01/08/2025] [Accepted: 01/21/2025] [Indexed: 01/28/2025]
Abstract
Mammalian sirtuins are class III histone deacetylases involved in the regulation of multiple biological processes including senescence, DNA repair, apoptosis, proliferation, caloric restriction, and metabolism. Among the mammalian sirtuins, SIRT3, SIRT4, and SIRT5 are localized in the mitochondria and collectively termed the mitochondrial sirtuins. Mitochondrial sirtuins are NAD+-dependent deacetylases that play a central role in cellular metabolism and function as epigenetic regulators by performing post-translational modification of cellular proteins. Several studies have identified the role of mitochondrial sirtuins in age-related pathologies and the rewiring of cancer metabolism. Mitochondrial sirtuins regulate cellular functions by contributing to post-translational modifications, including deacetylation, ADP-ribosylation, demalonylation, and desuccinylation of diverse cellular proteins to maintain cellular homeostasis. Here, we review and discuss the structure and function of the mitochondrial sirtuins and their role as metabolic regulators in breast cancer. Altered breast cancer metabolism may promote tumor progression and has been an essential target for therapy. Further, we discuss the potential role of targeting mitochondrial sirtuin and its impact on breast cancer progression using sirtuin inhibitors and activators as anticancer agents.
Collapse
Affiliation(s)
- Jesline Shaji Tharayil
- Department of Public Health Genomics, Centre for DNA Repair and Genome Stability (CDRGS), Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Amoolya Kandettu
- Department of Public Health Genomics, Centre for DNA Repair and Genome Stability (CDRGS), Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Sanjiban Chakrabarty
- Department of Public Health Genomics, Centre for DNA Repair and Genome Stability (CDRGS), Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
| |
Collapse
|
|
3
|
Alharbi B, Aldahlawi A, Assidi M, Basingab F, Zaher K, Alrahimi J, Mokhtar S, Al-Maghrabi J, Buhmeida A, Al-Sakkaf K. The Immunohistochemical Prognostic Value of Nuclear and Cytoplasmic Silent Information Regulator 1 Protein Expression in Saudi Patients with Breast Cancer. Biomolecules 2025; 15:50. [PMID: 39858444 PMCID: PMC11764178 DOI: 10.3390/biom15010050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 12/03/2024] [Accepted: 12/10/2024] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND The mammalian NAD-dependent deacetylase sirtuin-1 family (named also silent information regulator or SIRT family, where NAD stands for "nicotinamide adenine dinucleotide" (NAD)) appears to have a dual role in several human cancers by modulating cell proliferation and death. This study examines how SIRT1 protein levels correlate with clinicopathological characteristics and survival outcomes in patients with breast cancer. METHODS A total of 407 BC formalin-fixed paraffin-embedded (FFPE) samples were collected from King Abdulaziz University Hospital, Saudi Arabia. SIRT1 was stained on tissue microarray slides using automated immunohistochemistry. RESULTS All BC subtypes expressed more nuclear SIRT1 proteins than their cytoplasm counterparts. In luminal A, luminal B, and TNBC, nuclear and cytoplasmic SIRT1 were highly associated (p < 0.001). Kaplan-Meier analysis showed reduced disease-specific survival (DSS) in H2BC with high SIRT1 nuclear expression (p = 0.001, log-rank). Moreover, the cytoplasmic expression of SIRT1 in HER2-positive BC was associated with a larger tumor size (p = 0.036) and lymph node metastasis (p = 0.045). Nuclear SIRT1 expression was also positively associated with lymph node metastasis (LNM) (p = 0.048). As low-grade tumors had a higher frequency of SIRT1 protein expression than other groups, SIRT1 expression was associated with a favorable prognosis in patients with luminal A BC (p < 0.001). CONCLUSIONS SIRT1 expression seems to be involved in different molecular pathways either suppressing or promoting tumor growth depending on the subtype of BC. These molecular functions require further investigations and validation on larger BC cohorts.
Collapse
Affiliation(s)
- Bayan Alharbi
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia (S.M.)
- Laboratory, King Salman Medical City, Madinah 42319, Saudi Arabia
| | - Alia Aldahlawi
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia (F.B.)
- Immunology Unit, King Fahad for Medical Research, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia
| | - Mourad Assidi
- Institute of Genomic Medicine Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Fatemah Basingab
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia (F.B.)
- Immunology Unit, King Fahad for Medical Research, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia
| | - Kawther Zaher
- Immunology Unit, King Fahad for Medical Research, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia
| | - Jehan Alrahimi
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia (F.B.)
- Immunology Unit, King Fahad for Medical Research, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia
| | - Sara Mokhtar
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia (S.M.)
| | - Jaudah Al-Maghrabi
- Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Department of Pathology, King Faisal Specialist Hospital and Research Center, Jeddah 23433, Saudi Arabia
| | - Abdelbaset Buhmeida
- Institute of Genomic Medicine Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Kaltoom Al-Sakkaf
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia (S.M.)
- Immunology Unit, King Fahad for Medical Research, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia
| |
Collapse
|
|
4
|
Chatsirisupachai A, Muanjumpon P, Jeayeng S, Onkoksong T, Pluempreecha M, Soingam T, Panich U. Calcitriol/vitamin D receptor system alleviates PM2.5-induced human bronchial epithelial damage through upregulating mitochondrial bioenergetics in association with regulation of HIF-1α/PGC-1α signaling. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2024; 111:104568. [PMID: 39307374 DOI: 10.1016/j.etap.2024.104568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 09/07/2024] [Accepted: 09/19/2024] [Indexed: 09/27/2024]
Abstract
PM2.5 exposure causes lung injury by triggering oxidative stress, mitochondrial dysfunction, and modulating HIF-1α signaling. Calcitriol activates VDR, which regulates cellular homeostasis. This study evaluated the protective role of the calcitriol/VDR system in PM2.5-induced damage to BEAS-2B bronchial epithelial cells by reducing oxidative stress, upregulating mitochondrial bioenergetics, and downregulating HIF-1α. We found that the calcitriol/VDR system decreased ROS formation and restored mitochondrial bioenergetics in PM2.5-treated cells. This improvement correlated with reduced HIF-1α nuclear translocation and increased PGC-1α protein and mitochondrial gene expressions. This study is the first to suggest that targeting the calcitriol/VDR system could be a promising pharmacological strategy for mitigating PM2.5-induced lung epithelial damage by promoting mitochondrial bioenergetics and regulating PGC-1α and HIF-1α signaling.
Collapse
Affiliation(s)
| | - Phetthinee Muanjumpon
- Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Saowanee Jeayeng
- Department of Medical Science, School of Medicine, Walailak University, Nakhon Si Thammarat 80160, Thailand; Research Center in Tropical Pathobiology, Walailak University, Nakhon Si Thammarat 80160, Thailand
| | - Tasanee Onkoksong
- Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Mutita Pluempreecha
- Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Tanyapohn Soingam
- Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Uraiwan Panich
- Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
| |
Collapse
|
|
5
|
Trinh D, Al Halabi L, Brar H, Kametani M, Nash JE. The role of SIRT3 in homeostasis and cellular health. Front Cell Neurosci 2024; 18:1434459. [PMID: 39157755 PMCID: PMC11327144 DOI: 10.3389/fncel.2024.1434459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 06/25/2024] [Indexed: 08/20/2024] Open
Abstract
Mitochondria are responsible for maintaining cellular energy levels, and play a major role in regulating homeostasis, which ensures physiological function from the molecular to whole animal. Sirtuin 3 (SIRT3) is the major protein deacetylase of mitochondria. SIRT3 serves as a nutrient sensor; under conditions of mild metabolic stress, SIRT3 activity is increased. Within the mitochondria, SIRT3 regulates every complex of the electron transport chain, the tricarboxylic acid (TCA) and urea cycles, as well as the mitochondria membrane potential, and other free radical scavengers. This article reviews the role of SIRT3 in regulating homeostasis, and thus physiological function. We discuss the role of SIRT3 in regulating reactive oxygen species (ROS), ATP, immunological function and mitochondria dynamics.
Collapse
Affiliation(s)
- Dennison Trinh
- Department of Biological Sciences, University of Toronto, Toronto, ON, Canada
| | - Lina Al Halabi
- Department of Biological Sciences, University of Toronto, Toronto, ON, Canada
| | - Harsimar Brar
- Department of Biological Sciences, University of Toronto, Toronto, ON, Canada
| | - Marie Kametani
- Department of Biological Sciences, University of Toronto, Toronto, ON, Canada
| | - Joanne E. Nash
- Department of Biological Sciences, University of Toronto Scarborough Graduate Department of Cells Systems Biology, University of Toronto Cross-Appointment with Department of Psychology, University of Toronto Scarborough Scientist – KITE, Toronto, ON, Canada
| |
Collapse
|
|
6
|
Abdelmaksoud NM, Abulsoud AI, Abdelghany TM, Elshaer SS, Rizk SM, Senousy MA, Maurice NW. Uncovering SIRT3 and SHMT2-dependent pathways as novel targets for apigenin in modulating colorectal cancer: In vitro and in vivo studies. Exp Cell Res 2024; 441:114150. [PMID: 38971519 DOI: 10.1016/j.yexcr.2024.114150] [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: 05/31/2024] [Revised: 06/29/2024] [Accepted: 07/03/2024] [Indexed: 07/08/2024]
Abstract
Despite significant advances in the treatment of colorectal cancer (CRC), identification of novel targets and treatment options are imperative for improving its prognosis and survival rates. The mitochondrial SIRT3 and SHMT2 have key roles in metabolic reprogramming and cell proliferation. This study investigated the potential use of the natural product apigenin in CRC treatment employing both in vivo and in vitro models and explored the role of SIRT3 and SHMT2 in apigenin-induced CRC apoptosis. The role of SHMT2 in CRC patients' survival was verified using TCGA database. In vivo, apigenin treatment restored the normal colon appearance. On the molecular level, apigenin augmented the immunohistochemical expression of cleaved caspase-3 and attenuated SIRT3 and SHMT2 mRNA expression CRC patients with decreased SHMT2 expression had improved overall and disease-free survival rates. In vitro, apigenin reduced the cell viability in a time-dependent manner, induced G0/G1 cell cycle arrest, and increased the apoptotic cell population compared to the untreated control. Mechanistically, apigenin treatment mitigated the expression of SHMT2, SIRT3, and its upstream long intergenic noncoding RNA LINC01234 in CRC cells. Conclusively, apigenin induces caspase-3-dependent apoptosis in CRC through modulation of SIRT3-triggered mitochondrial pathway suggesting it as a promising therapeutic agent to improve patient outcomes.
Collapse
Affiliation(s)
- Nourhan M Abdelmaksoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020, El Salam, 11785, Cairo, Egypt
| | - Ahmed I Abulsoud
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11823, Egypt; Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020, El Salam, 11785, Cairo, Egypt.
| | - Tamer M Abdelghany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11884, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020, El Salam, 11785, Cairo, Egypt
| | - Shereen Saeid Elshaer
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020, El Salam, 11785, Cairo, Egypt; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, 11823, Egypt
| | - Sherine Maher Rizk
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
| | - Mahmoud A Senousy
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt; Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, 11786, Egypt
| | - Nadine W Maurice
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
| |
Collapse
|
|
7
|
Wang Y. The interplay of exercise and polyphenols in cancer treatment: A focus on oxidative stress and antioxidant mechanisms. Phytother Res 2024; 38:3459-3488. [PMID: 38690720 DOI: 10.1002/ptr.8215] [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: 02/01/2024] [Revised: 04/12/2024] [Accepted: 04/14/2024] [Indexed: 05/02/2024]
Abstract
Exercise has been demonstrated to induce an elevated production of free radicals, leading to the onset of oxidative stress. Numerous studies highlight the positive impacts of aerobic exercise, primarily attributed to the increase in overall antioxidant capacity. The evidence suggests that engaging in aerobic exercise contributes to a reduction in the likelihood of advanced cancer and mortality. Oxidative stress occurs when there is an imbalance between the generation of free radicals and the collective antioxidant defense system, encompassing both enzymatic and nonenzymatic antioxidants. Typically, oxidative stress triggers the formation of reactive oxygen or nitrogen species, instigating or advancing various issues in cancers and other diseases. The pro-oxidant-antioxidant balance serves as a direct measure of this imbalance in oxidative stress. Polyphenols contain a variety of bioactive compounds, including flavonoids, flavanols, and phenolic acids, conferring antioxidant properties. Previous research highlights the potential of polyphenols as antioxidants, with documented effects on reducing cancer risk by influencing processes such as proliferation, angiogenesis, and metastasis. This is primarily attributed to their recognized antioxidant capabilities. Considering the extensive array of signaling pathways associated with exercise and polyphenols, this overview will specifically focus on oxidative stress, the antioxidant efficacy of polyphenols and exercise, and their intricate interplay in cancer treatment.
Collapse
Affiliation(s)
- Yubing Wang
- College of Physical Education, Qilu Normal University, Jinan, Shandong, China
| |
Collapse
|
|
8
|
Aventaggiato M, Arcangeli T, Vernucci E, Barreca F, Sansone L, Pellegrini L, Pontemezzo E, Valente S, Fioravanti R, Russo MA, Mai A, Tafani M. Pharmacological Activation of SIRT3 Modulates the Response of Cancer Cells to Acidic pH. Pharmaceuticals (Basel) 2024; 17:810. [PMID: 38931477 DOI: 10.3390/ph17060810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 06/14/2024] [Accepted: 06/17/2024] [Indexed: 06/28/2024] Open
Abstract
Cancer cells modulate their metabolism, creating an acidic microenvironment that, in turn, can favor tumor progression and chemotherapy resistance. Tumor cells adopt strategies to survive a drop in extracellular pH (pHe). In the present manuscript, we investigated the contribution of mitochondrial sirtuin 3 (SIRT3) to the adaptation and survival of cancer cells to a low pHe. SIRT3-overexpressing and silenced breast cancer cells MDA-MB-231 and human embryonic kidney HEK293 cells were grown in buffered and unbuffered media at pH 7.4 and 6.8 for different times. mRNA expression of SIRT3 and CAVB, was measured by RT-PCR. Protein expression of SIRT3, CAVB and autophagy proteins was estimated by western blot. SIRT3-CAVB interaction was determined by immunoprecipitation and proximity ligation assays (PLA). Induction of autophagy was studied by western blot and TEM. SIRT3 overexpression increases the survival of both cell lines. Moreover, we demonstrated that SIRT3 controls intracellular pH (pHi) through the regulation of mitochondrial carbonic anhydrase VB (CAVB). Interestingly, we obtained similar results by using MC2791, a new SIRT3 activator. Our results point to the possibility of modulating SIRT3 to decrease the response and resistance of tumor cells to the acidic microenvironment and ameliorate the effectiveness of anticancer therapy.
Collapse
Affiliation(s)
- Michele Aventaggiato
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Tania Arcangeli
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Enza Vernucci
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Federica Barreca
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Luigi Sansone
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Via di Val Cannuta 247, 00166 Rome, Italy
- Laboratory of Cellular and Molecular Pathology, IRCCS San Raffaele Rome, Via di Val Cannuta 247, 00166 Rome, Italy
| | - Laura Pellegrini
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Elena Pontemezzo
- European Hospital, New Fertility Group, Center for Reproductive Medicine, Via Portuense 700, 00149 Rome, Italy
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Rossella Fioravanti
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Matteo Antonio Russo
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Via di Val Cannuta 247, 00166 Rome, Italy
- Laboratory of Cellular and Molecular Pathology, IRCCS San Raffaele Rome, Via di Val Cannuta 247, 00166 Rome, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Marco Tafani
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| |
Collapse
|
|
9
|
Zeng Y, Zhang Y, Cui Z, Mao J, Xu J, Yao R. The Selective SIRT3 Inhibitor 3-TYP Represses Primary Myeloma Growth by Reducing c-Myc Stability. Chem Res Toxicol 2024; 37:1062-1069. [PMID: 38815162 DOI: 10.1021/acs.chemrestox.4c00142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2024]
Abstract
Multiple myeloma is a hematological cancer that can be treated but remains incurable. With the advancement of science and technology, more drugs have been developed for myeloma chemotherapy that greatly improve the quality of life of patients. However, relapse remains a serious problem puzzling patients and doctors. Thus, developing more highly active and specific inhibitors is urgent for myeloma-targeted therapy. In this study, we identified the SIRT3 inhibitor 3-TYP (3-(1H-1,2,3-triazol-4-yl) pyridine) after screening a histone modification compound library, which showed high cytotoxicity and induced DNA damage in myeloma cells. Furthermore, the inhibitory effect of 3-TYP in our xenograft tumor studies also confirmed that compound 3-TYP could inhibit primary myeloma growth by reducing c-Myc protein stability by decreasing c-Myc Ser62 phosphorylation levels. Taken together, the results of our study identified 3-TYP as a novel c-Myc inhibitor, which could be a potential chemotherapeutic agent to target multiple myeloma.
Collapse
Affiliation(s)
- Yindi Zeng
- Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Yaxin Zhang
- Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Zeyu Cui
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Jiwei Mao
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Jinge Xu
- The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
| | - Ruosi Yao
- Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| |
Collapse
|
|
10
|
Yu L, Li Y, Song S, Zhang Y, Wang Y, Wang H, Yang Z, Wang Y. The dual role of sirtuins in cancer: biological functions and implications. Front Oncol 2024; 14:1384928. [PMID: 38947884 PMCID: PMC11211395 DOI: 10.3389/fonc.2024.1384928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Accepted: 05/30/2024] [Indexed: 07/02/2024] Open
Abstract
Sirtuins are pivotal in orchestrating numerous cellular pathways, critically influencing cell metabolism, DNA repair, aging processes, and oxidative stress. In recent years, the involvement of sirtuins in tumor biology has garnered substantial attention, with a growing body of evidence underscoring their regulatory roles in various aberrant cellular processes within tumor environments. This article delves into the sirtuin family and its biological functions, shedding light on their dual roles-either as promoters or inhibitors-in various cancers including oral, breast, hepatocellular, lung, and gastric cancers. It further explores potential anti-tumor agents targeting sirtuins, unraveling the complex interplay between sirtuins, miRNAs, and chemotherapeutic drugs. The dual roles of sirtuins in cancer biology reflect the complexity of targeting these enzymes but also highlight the immense therapeutic potential. These advancements hold significant promise for enhancing clinical outcomes, marking a pivotal step forward in the ongoing battle against cancer.
Collapse
Affiliation(s)
- Lu Yu
- Department of Respiratory, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yanjiao Li
- Department of Pharmacy, Qionglai Hospital of Traditional Chinese Medicine, Chengdu, China
| | - Siyuan Song
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Yalin Zhang
- School of Medicine, University of Electronic Science and Technology of China, Center of Critical Care Medicine, Sichuan Academy of Medical Sciences, Chengdu, China
- Center of Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yiping Wang
- Center of Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Hailian Wang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science, Nanning, China
| | - Zhengteng Yang
- Department of Medicine, The First Affiliated Hospital of Guangxi University of Traditional Medicine, Nanning, China
| | - Yi Wang
- Center of Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science, Nanning, China
| |
Collapse
|
|
11
|
Huang Y, Zhang R, Lyu H, Xiao S, Guo D, Chen XZ, Zhou C, Tang J. LncRNAs as nodes for the cross-talk between autophagy and Wnt signaling in pancreatic cancer drug resistance. Int J Biol Sci 2024; 20:2698-2726. [PMID: 38725864 PMCID: PMC11077374 DOI: 10.7150/ijbs.91832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 02/06/2024] [Indexed: 05/12/2024] Open
Abstract
Pancreatic cancer is a malignancy with high mortality. In addition to the few symptoms until the disease reaches an advanced stage, the high fatality rate is attributed to its rapid development, drug resistance and lack of appropriate treatment. In the selection and research of therapeutic drugs, gemcitabine is the first-line drug for pancreatic cancer. Solving the problem of gemcitabine resistance in pancreatic cancer will contribute to the progress of pancreatic cancer treatment. Long non coding RNAs (lncRNAs), which are RNA transcripts longer than 200 nucleotides, play vital roles in cellular physiological metabolic activities. Currently, our group and others have found that some lncRNAs are aberrantly expressed in pancreatic cancer cells, which can regulate the process of cancer through autophagy and Wnt/β-catenin pathways simultaneously and affect the sensitivity of cancer cells to therapeutic drugs. This review presents an overview of the recent evidence concerning the node of lncRNA for the cross-talk between autophagy and Wnt/β-catenin signaling in pancreatic cancer, together with the practicability of lncRNAs and the core regulatory factors as targets in therapeutic resistance.
Collapse
Affiliation(s)
- Yuhan Huang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China, 430068
| | - Rui Zhang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China, 430068
| | - Hao Lyu
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China, 430068
| | - Shuai Xiao
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China, 430068
| | - Dong Guo
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China, 430068
| | - Xing-Zhen Chen
- Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada, T6G2R3
| | - Cefan Zhou
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China, 430068
| | - Jingfeng Tang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China, 430068
| |
Collapse
|
|
12
|
Li Y, Yang L, Su P, Chen N. Curcumin protects against cadmium-induced germ cell death in the testis of rats. Toxicol Res (Camb) 2024; 13:tfae082. [PMID: 38841432 PMCID: PMC11149375 DOI: 10.1093/toxres/tfae082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 03/26/2024] [Accepted: 05/10/2024] [Indexed: 06/07/2024] Open
Abstract
Introduction Cadmium (Cd) has been shown to disrupt the reproductive system. In this study, we evaluated the protective effects of Curcumin (Cur) against Cd-induced reproductive toxicity. Methods Exploring the role of Cur in Cd-treated rat models. Results The study demonstrated that Cd treatment impaired the seminiferous epithelium, leading to increased apoptosis of germ cells. Interestingly, pretreatment with Cur ameliorated the histological damage and decreased the germ cell apoptosis induced by Cd. Furthermore, after Cd exposure, B-cell lymphoma-2 expression was significantly decreased while Bax expression was increased. Pretreatment of rats with Cur protected against germ cell apoptosis by improving the expression of B-cell lymphoma-2 and reducing Bax. Additionally, Cd treatment increased reactive oxygen species, resulting in a decrease in antioxidant enzymes. However, pretreatment of rats with Cur followed by Cd administration led to a substantial decrease in reactive oxygen species levels and increased activities of antioxidant enzymes. Ultrastructural investigations revealed that damage to the mitochondrial structure was significantly ameliorated by Cur pretreatment in Cd-treated rats. Notably, Cur significantly activated the peroxisome proliferator-activated receptor gamma coactivator 1a/Sirtuins-3 signaling pathway. Conclusions Overall, our data suggest that Cd induces germ cell apoptosis through mitochondrial-induced oxidative stress, but Cur pretreatment offers strong protection against Cd-induced reproductive toxicity.
Collapse
Affiliation(s)
- Yamin Li
- Department of Woman's Health Care, Maternal and Child Health Hospital of Hubei Province, 745 Luoyu Avenue, Wuhan, Hubei 430071, P. R. China
| | - Lu Yang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, P. R. China
| | - Ping Su
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, 13 HangkongAvenue, Wuhan 430030, P. R. China
| | - Na Chen
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, P. R. China
| |
Collapse
|
|
13
|
Belužić R, Šimunić E, Podgorski II, Pinterić M, Hadžija MP, Balog T, Sobočanec S. Gene Expression Profiling Reveals Fundamental Sex-Specific Differences in SIRT3-Mediated Redox and Metabolic Signaling in Mouse Embryonic Fibroblasts. Int J Mol Sci 2024; 25:3868. [PMID: 38612678 PMCID: PMC11012119 DOI: 10.3390/ijms25073868] [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: 02/27/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
Sirt-3 is an important regulator of mitochondrial function and cellular energy homeostasis, whose function is associated with aging and various pathologies such as Alzheimer's disease, Parkinson's disease, cardiovascular diseases, and cancers. Many of these conditions show differences in incidence, onset, and progression between the sexes. In search of hormone-independent, sex-specific roles of Sirt-3, we performed mRNA sequencing in male and female Sirt-3 WT and KO mouse embryonic fibroblasts (MEFs). The aim of this study was to investigate the sex-specific cellular responses to the loss of Sirt-3. By comparing WT and KO MEF of both sexes, the differences in global gene expression patterns as well as in metabolic and stress responses associated with the loss of Sirt-3 have been elucidated. Significant differences in the activities of basal metabolic pathways were found both between genotypes and between sexes. In-depth pathway analysis of metabolic pathways revealed several important sex-specific phenomena. Male cells mount an adaptive Hif-1a response, shifting their metabolism toward glycolysis and energy production from fatty acids. Furthermore, the loss of Sirt-3 in male MEFs leads to mitochondrial and endoplasmic reticulum stress. Since Sirt-3 knock-out is permanent, male cells are forced to function in a state of persistent oxidative and metabolic stress. Female MEFs are able to at least partially compensate for the loss of Sirt-3 by a higher expression of antioxidant enzymes. The activation of neither Hif-1a, mitochondrial stress response, nor oxidative stress response was observed in female cells lacking Sirt-3. These findings emphasize the sex-specific role of Sirt-3, which should be considered in future research.
Collapse
|
|
14
|
Lambona C, Zwergel C, Valente S, Mai A. SIRT3 Activation a Promise in Drug Development? New Insights into SIRT3 Biology and Its Implications on the Drug Discovery Process. J Med Chem 2024; 67:1662-1689. [PMID: 38261767 PMCID: PMC10859967 DOI: 10.1021/acs.jmedchem.3c01979] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/14/2023] [Accepted: 12/20/2023] [Indexed: 01/25/2024]
Abstract
Sirtuins catalyze deacetylation of lysine residues with a NAD+-dependent mechanism. In mammals, the sirtuin family is composed of seven members, divided into four subclasses that differ in substrate specificity, subcellular localization, regulation, as well as interactions with other proteins, both within and outside the epigenetic field. Recently, much interest has been growing in SIRT3, which is mainly involved in regulating mitochondrial metabolism. Moreover, SIRT3 seems to be protective in diseases such as age-related, neurodegenerative, liver, kidney, heart, and metabolic ones, as well as in cancer. In most cases, activating SIRT3 could be a promising strategy to tackle these health problems. Here, we summarize the main biological functions, substrates, and interactors of SIRT3, as well as several molecules reported in the literature that are able to modulate SIRT3 activity. Among the activators, some derive from natural products, others from library screening, and others from the classical medicinal chemistry approach.
Collapse
Affiliation(s)
- Chiara Lambona
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Clemens Zwergel
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Sergio Valente
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Antonello Mai
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
- Pasteur
Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| |
Collapse
|
|
15
|
Liu Y, Wei H, Li J. A review on SIRT3 and its natural small molecule activators as a potential Preventive and therapeutic target. Eur J Pharmacol 2024; 963:176155. [PMID: 37914065 DOI: 10.1016/j.ejphar.2023.176155] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 11/03/2023]
Abstract
Sirtuins (SIRTs) were originally characterized by yeast Sir2 as a lifespan regulator that is conserved in all three structural domains of bacteria, archaea and eukaryotes and belong to histone deacetylases consisting of seven members (SIRT1-SIRT7). Surprisingly, SIRTs have been shown to play important regulatory roles in almost all cellular functions, including mitochondrial biogenesis, oxidative stress, inflammation, cell growth, energy metabolism, neural function, and stress resistance. Among the SIRT members, sirtuin 3 (SIRT3) is one of the most important deacetylases that regulates the mitochondrial acetylation and plays a role in pathological processes, such as metabolism, DNA repair, oxidative stress, apoptosis and ferroptosis. Therefore, SIRT3 is considered as a potential target for the treatment of a variety of pathological diseases, including metabolic diseases, neurodegenerative diseases, age-related diseases and others. Furthermore, the isolation, screening, and development of SIRT3 signaling agonists, especially from natural products, have become a widely investigated objective. This paper describes the structure of SIRT3 protein, discusses the pathological process of SIRT3-mediated acetylation modification, and reviews the role of SIRT3 in diseases, SIRT3 activators and its related disease studies.
Collapse
Affiliation(s)
- Yuanyuan Liu
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Haidong Wei
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China.
| | - Jianhong Li
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China; Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin, 150030, China.
| |
Collapse
|
|
16
|
Jun JH, Kim JS, Palomera LF, Jo DG. Dysregulation of histone deacetylases in ocular diseases. Arch Pharm Res 2024; 47:20-39. [PMID: 38151648 DOI: 10.1007/s12272-023-01482-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 12/20/2023] [Indexed: 12/29/2023]
Abstract
Ocular diseases are a growing global concern and have a significant impact on the quality of life. Cataracts, glaucoma, age-related macular degeneration, and diabetic retinopathy are the most prevalent ocular diseases. Their prevalence and the global market size are also increasing. However, the available pharmacotherapy is currently limited. These diseases share common pathophysiological features, including neovascularization, inflammation, and/or neurodegeneration. Histone deacetylases (HDACs) are a class of enzymes that catalyze the removal of acetyl groups from lysine residues of histone and nonhistone proteins. HDACs are crucial for regulating various cellular processes, such as gene expression, protein stability, localization, and function. They have also been studied in various research fields, including cancer, inflammatory diseases, neurological disorders, and vascular diseases. Our study aimed to investigate the relationship between HDACs and ocular diseases, to identify a new strategy for pharmacotherapy. This review article explores the role of HDACs in ocular diseases, specifically focusing on diabetic retinopathy, age-related macular degeneration, and retinopathy of prematurity, as well as optic nerve disorders, such as glaucoma and optic neuropathy. Additionally, we explore the interplay between HDACs and key regulators of fibrosis and angiogenesis, such as TGF-β and VEGF, highlighting the potential of targeting HDAC as novel therapeutic strategies for ocular diseases.
Collapse
Affiliation(s)
- Jae Hyun Jun
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Korea
- Department of Pharmacology, CKD Research Institute, Chong Kun Dang Pharmaceutical Co., Yongin, 16995, Korea
| | - Jun-Sik Kim
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Korea
| | - Leon F Palomera
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Korea
| | - Dong-Gyu Jo
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Korea.
- Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 06351, Korea.
- Biomedical Institute for Convergence, Sungkyunkwan University, Suwon, 16419, Korea.
| |
Collapse
|
|
17
|
Zhao Y, Tang H, Kuai Y, Xu J, Sun B, Li Y. Identification of the function of FOSB in cholangiocarcinoma using bioinformatics analysis. Transl Cancer Res 2023; 12:3629-3640. [PMID: 38192979 PMCID: PMC10774044 DOI: 10.21037/tcr-23-829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 09/28/2023] [Indexed: 01/10/2024]
Abstract
Background Exploring the potential mechanism of cholangiocarcinoma (CCA) metabolic reprogramming is significant for guiding clinical treatment. However, related research and exploration are still lacking. Therefore, we aimed to identify a reliable metabolism-related gene or biomarker of CCA using bioinformatics analysis. Methods The GSE26566, GSE45001, and GSE132305 datasets were obtained from the Gene Expression Omnibus (GEO) database. Differently expressed genes (DEGs) between CCA tissues and adjacent tissues were screened out. The key gene was identified through enrichment and functional analysis, and its immune and clinical correlation was investigated utilizing the Tumor Immune Evaluation Resource (TIMER2.0), the Tumor-Immune System Interactions Database (TISIDB), the Gene Expression Profiling Interactive Analysis (GEPIA2), and the Kaplan-Meier Plotter. Finally, immunohistochemistry (IHC) was performed to validate the results. Results By analysis, the expression of FBJ murine osteosarcoma viral oncogene homolog B (FOSB) was significantly downregulated in CCA tissues when compared with adjacent tissues. Moreover, the expression levels of FOSB positively correlated with tumor-infiltrating immune cells in most tumors, and patients with high FOSB expression tended to have a better prognosis. The FOSB and SIRT3/HIF1A axes have similar expression trends and metabolic functions in CCA cells, and the correlation between of them was preliminarily explored by IHC experiments. Conclusions The expression levels of FOSB are closely related to the prognosis of CCA patients, which may be a predictive indicator for prognosis and immunotherapy.
Collapse
Affiliation(s)
- Yihang Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hong Tang
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yaxian Kuai
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jianhua Xu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Bin Sun
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yang Li
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| |
Collapse
|
|
18
|
Minisini M, Cricchi E, Brancolini C. Acetylation and Phosphorylation in the Regulation of Hypoxia-Inducible Factor Activities: Additional Options to Modulate Adaptations to Changes in Oxygen Levels. Life (Basel) 2023; 14:20. [PMID: 38276269 PMCID: PMC10821055 DOI: 10.3390/life14010020] [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: 12/05/2023] [Revised: 12/13/2023] [Accepted: 12/20/2023] [Indexed: 01/27/2024] Open
Abstract
O2 is essential for the life of eukaryotic cells. The ability to sense oxygen availability and initiate a response to adapt the cell to changes in O2 levels is a fundamental achievement of evolution. The key switch for adaptation consists of the transcription factors HIF1A, HIF2A and HIF3A. Their levels are tightly controlled by O2 through the involvement of the oxygen-dependent prolyl hydroxylase domain-containing enzymes (PHDs/EGNLs), the von Hippel-Lindau tumour suppressor protein (pVHL) and the ubiquitin-proteasome system. Furthermore, HIF1A and HIF2A are also under the control of additional post-translational modifications (PTMs) that positively or negatively regulate the activities of these transcription factors. This review focuses mainly on two PTMs of HIF1A and HIF2A: phosphorylation and acetylation.
Collapse
Affiliation(s)
| | | | - Claudio Brancolini
- Lab of Epigenomics, Department of Medicine, Università degli Studi di Udine, 33100 Udine, Italy; (M.M.); (E.C.)
| |
Collapse
|
|
19
|
Huang B, Ding J, Guo H, Wang H, Xu J, Zheng Q, Zhou L. SIRT3 Regulates the ROS-FPR1/HIF-1α Axis under Hypoxic Conditions to Influence Lung Cancer Progression. Cell Biochem Biophys 2023; 81:813-821. [PMID: 37747648 PMCID: PMC10611604 DOI: 10.1007/s12013-023-01180-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 09/17/2023] [Indexed: 09/26/2023]
Abstract
Hypoxia-inducible factor (HIF-1α) is a therapeutic target in lung cancer, and the deacetylase sirtuin 3 (SIRT3) is closely associated with tumorigenesis. Formyl peptide receptor 1 (FPR1) is involved in a wide range of physiopathological processes in various tumor cells. We explored whether SIRT3 affects the development of lung cancer by regulating the reactive oxygen species (ROS)-FPR1/HIF-1α axis under hypoxic conditions. The effects of SIRT3 overexpression on the levels of FPR1, HIF-1α, ROS, inflammatory factors, and cell proliferation and migration in A549 cells under hypoxic conditions were assessed in combination with the FPR1 inhibitor. BALB/c nude mice were subcutaneously injected with cancer cells transfected/untransfected with SIRT3 overexpressing lentiviral vectors. Immunohistochemistry and enzyme-linked immunosorbent assay were performed to detect SIRT3 expression and the expression levels of IL-1β, TNF-α, and IL-6, respectively, in tumor tissues. Cell proliferation, invasion, migration, and IL-1β, TNF-α, IL-6, and ROS levels were significantly higher in the Hypoxia group than in the Control group. Moreover, the mRNA and protein expression levels of SIRT3 were significantly down-regulated, whereas they were significantly up-regulated for FPR1 and HIF-1α. In contrast, SIRT3 overexpression in a hypoxic environment inhibited cell proliferation, invasion, and migration, decreased IL-1β, TNF-α, IL-6, and ROS levels, up-regulated the mRNA and protein expression levels of SIRT3, and down-regulated the mRNA and protein expression levels of FPR1 and HIF-1α. In addition, we found the same results in tumorigenic experiments in nude mice. SIRT3 in hypoxic environments may affect tumor cell proliferation, invasion, migration, and inflammation levels via the ROS-FPR1/HIF-1α axis, thereby inhibiting tumor cell development.
Collapse
Affiliation(s)
- Bo Huang
- Wuhan Third Hospital/Tongren Hospital of Wuhan University, Wuhan East Lake High-Tech Development Zone Jiufeng Street Center City Community Health Service Center, Wuhan, 430074, Hubei, China.
| | - Jie Ding
- Wuhan Third Hospital/Tongren Hospital of Wuhan University, Wuhan, 430074, Hubei, China
| | - HongRong Guo
- Wuhan Third Hospital/Tongren Hospital of Wuhan University, Wuhan, 430074, Hubei, China
| | - HongJuan Wang
- Wuhan Third Hospital/Tongren Hospital of Wuhan University, Wuhan, 430074, Hubei, China
| | - JianQun Xu
- Wuhan Third Hospital/Tongren Hospital of Wuhan University, Wuhan, 430074, Hubei, China
| | - Quan Zheng
- Wuhan Third Hospital/Tongren Hospital of Wuhan University, Wuhan, 430074, Hubei, China
| | - LiJun Zhou
- Wuhan Third Hospital/Tongren Hospital of Wuhan University, Wuhan, 430074, Hubei, China
| |
Collapse
|
|
20
|
Deng Y, Cheng Q, He J. HDAC inhibitors: Promising agents for leukemia treatment. Biochem Biophys Res Commun 2023; 680:61-72. [PMID: 37722346 DOI: 10.1016/j.bbrc.2023.09.023] [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: 07/26/2023] [Revised: 09/04/2023] [Accepted: 09/11/2023] [Indexed: 09/20/2023]
Abstract
The essential role of epigenetic modification in the pathogenesis of a series of cancers have gradually been recognized. Histone deacetylase (HDACs), as well-known epigenetic modulators, are responsible for DNA repair, cell proliferation, differentiation, apoptosis and angiogenesis. Studies have shown that aberrant expression of HDACs is found in many cancer types. Thus, inhibition of HDACs has provided a promising therapeutic approach alternative for these patients. Since HDAC inhibitor (HDACi) vorinostat was first approved by the Food and Drug Administration (FDA) for treating cutaneous T-cell lymphoma (CTCL) in 2006, the combination of HDAC inhibitors with other molecules such as chemotherapeutic drugs has drawn much attention in current cancer treatment, especially in hematological malignancies therapy. Up to now, there have been more than twenty HDAC inhibitors investigated in clinic trials with five approvals being achieved. Indeed, Histone deacetylase inhibitors promote or enhance several different anticancer mechanisms and therefore are in evidence as potential antileukemia agents. In this review, we will focus on possible mechanisms by how HDAC inhibitors exert therapeutic benefit and their clinical utility in leukemia.
Collapse
Affiliation(s)
- Yun Deng
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Cheng
- Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Jing He
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| |
Collapse
|
|
21
|
Azzam HN, El-Derany MO, Wahdan SA, Faheim RM, Helal GK, El-Demerdash E. The role of mitochondrial/metabolic axis in development of tamoxifen resistance in breast cancer. Hum Cell 2023; 36:1877-1886. [PMID: 37646973 PMCID: PMC10587280 DOI: 10.1007/s13577-023-00977-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 08/20/2023] [Indexed: 09/01/2023]
Abstract
Only a few investigations, to our knowledge, have examined the bioenergetics of Tamoxifen (TMX) resistant individuals and reported altered mitochondrial activity and metabolic profile. The primary cause of TMX resistance is firmly suggested to be metabolic changes. Metabolic variations and hypoxia have also been linked in a bidirectional manner. Increased hypoxic levels correlate with early recurrence and proliferation and have a negative therapeutic impact on breast cancer (BC) patients. Hypoxia, carcinogenesis, and patient death are all correlated, resulting in more aggressive traits, a higher chance of metastasis, and TMX resistance. Consequently, we sought to investigate the possible role of the metabolic/hypoxial axis Long non-coding RNA (LncRNA) Taurine up-regulated 1 (TUG-1), Micro-RNA 186-5p (miR-186), Sirtuin-3 (SIRT3), Peroxisome Proliferator Activator Receptor alpha (PPAR-α), and Hypoxia-Inducible Factor-1 (HIF-1) in the development of TMX resistance in BC patients and to correlate this axis with tumor progression. Interestingly, this will be the first time to explore epigenetic regulation of this axis in BC.
Collapse
Affiliation(s)
- Hany N Azzam
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt
| | - Marwa O El-Derany
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Sara A Wahdan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Reham M Faheim
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Gouda K Helal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Ebtehal El-Demerdash
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
- Preclinical & Translational Research Center, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
| |
Collapse
|
|
22
|
Pezzotta A, Perico L, Corna D, Morigi M, Remuzzi G, Benigni A, Imberti B. Sirt3 deficiency promotes endothelial dysfunction and aggravates renal injury. PLoS One 2023; 18:e0291909. [PMID: 37816025 PMCID: PMC10564163 DOI: 10.1371/journal.pone.0291909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 09/07/2023] [Indexed: 10/12/2023] Open
Abstract
Sirtuin 3 (SIRT3), the main deacetylase of mitochondria, modulates the acetylation levels of substrates governing metabolism and oxidative stress. In the kidney, we showed that SIRT3 affects the proper functioning of high energy-demanding cells, such as tubular cells and podocytes. Less is known about the role of SIRT3 in regulating endothelial cell function and its impact on the progression of kidney disease. Here, we found that whole body Sirt3-deficient mice exhibited reduced renal capillary density, reflecting endothelial dysfunction, and VEGFA expression compared to wild-type mice. This was paralleled by activation of hypoxia signaling, upregulation of HIF-1α and Angiopietin-2, and oxidative stress increase. These alterations did not result in kidney disease. However, when Sirt3-deficient mice were exposed to the nephrotoxic stimulus Adriamycin (ADR) they developed aggravated endothelial rarefaction, altered VEGFA signaling, and higher oxidative stress compared to wild-type mice receiving ADR. As a result, ADR-treated Sirt3-deficient mice experienced a more severe injury with exacerbated albuminuria, podocyte loss and fibrotic lesions. These data suggest that SIRT3 is a crucial regulator of renal vascular homeostasis and its dysregulation is a predisposing factor for kidney disease. By extension, our findings indicate SIRT3 as a pharmacologic target in progressive renal disease whose treatments are still imperfect.
Collapse
Affiliation(s)
- Anna Pezzotta
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Luca Perico
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Daniela Corna
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Marina Morigi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Ariela Benigni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Barbara Imberti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| |
Collapse
|
|
23
|
Andriolo LG, Cammisotto V, Spagnoli A, Alunni Fegatelli D, Chicone M, Di Rienzo G, Dell’Anna V, Lobreglio G, Serio G, Pignatelli P. Overview of angiogenesis and oxidative stress in cancer. World J Meta-Anal 2023; 11:253-265. [DOI: 10.13105/wjma.v11.i6.253] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/07/2023] [Accepted: 07/10/2023] [Indexed: 09/13/2023] Open
Abstract
Neoplasms can be considered as a group of aberrant cells that need more vascular supply to fulfill all their functions. Therefore, they promote angiogenesis through the same neovascularization pathway used physiologically. Angiogenesis is a process characterized by a heterogeneous distribution of oxygen caused by the tumor and oxidative stress; the latter being one of the most powerful stimuli of angiogenesis. As a result of altered tumor metabolism due to hypoxia, acidosis occurs. The angiogenic process and oxidative stress can be detected by measuring serum and tissue biomarkers. The study of the mechanisms underlying angiogenesis and oxidative stress could lead to the identification of new biomarkers, ameliorating the selection of patients with neoplasms and the prediction of their response to possible anti-tumor therapies. In particular, in the treatment of patients with similar clinical tumor phenotypes but different prognoses, the new biomarkers could be useful. Moreover, they may lead to a better understanding of the mechanisms underlying drug resistance. Experimental studies show that blocking the vascular supply results in antiproliferative activity in vivo in neuroendocrine tumor cells, which require a high vascular supply.
Collapse
Affiliation(s)
- Luigi Gaetano Andriolo
- Department of General and Specialistic Surgery Paride Stefanini, Policlinico Umberto I, University of Rome Sapienza, Rome 06100, Italy
- Unità Operativa Complessa Chirurgia Toracica, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Vittoria Cammisotto
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, University of Rome Sapienza, Rome 06100, Italy
| | - Alessandra Spagnoli
- Department of Public Health and Infectious Diseases, University of Rome Sapienza, Rome 06100, Italy
| | - Danilo Alunni Fegatelli
- Department of Public Health and Infectious Diseases, University of Rome Sapienza, Rome 06100, Italy
| | - Michele Chicone
- Department of Clinical Pathology and Microbiology, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Gaetano Di Rienzo
- Unità Operativa Complessa Chirurgia Toracica, Ospedale Vito Fazzi, Lecce 73100, Italy
| | | | - Giambattista Lobreglio
- Department of Clinical Pathology and Microbiology, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Giovanni Serio
- Pathological Anatomy Unit, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, University of Rome Sapienza, Rome 06100, Italy
| |
Collapse
|
|
24
|
Pendleton KE, Wang K, Echeverria GV. Rewiring of mitochondrial metabolism in therapy-resistant cancers: permanent and plastic adaptations. Front Cell Dev Biol 2023; 11:1254313. [PMID: 37779896 PMCID: PMC10534013 DOI: 10.3389/fcell.2023.1254313] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/28/2023] [Indexed: 10/03/2023] Open
Abstract
Deregulation of tumor cell metabolism is widely recognized as a "hallmark of cancer." Many of the selective pressures encountered by tumor cells, such as exposure to anticancer therapies, navigation of the metastatic cascade, and communication with the tumor microenvironment, can elicit further rewiring of tumor cell metabolism. Furthermore, phenotypic plasticity has been recently appreciated as an emerging "hallmark of cancer." Mitochondria are dynamic organelles and central hubs of metabolism whose roles in cancers have been a major focus of numerous studies. Importantly, therapeutic approaches targeting mitochondria are being developed. Interestingly, both plastic (i.e., reversible) and permanent (i.e., stable) metabolic adaptations have been observed following exposure to anticancer therapeutics. Understanding the plastic or permanent nature of these mechanisms is of crucial importance for devising the initiation, duration, and sequential nature of metabolism-targeting therapies. In this review, we compare permanent and plastic mitochondrial mechanisms driving therapy resistance. We also discuss experimental models of therapy-induced metabolic adaptation, therapeutic implications for targeting permanent and plastic metabolic states, and clinical implications of metabolic adaptations. While the plasticity of metabolic adaptations can make effective therapeutic treatment challenging, understanding the mechanisms behind these plastic phenotypes may lead to promising clinical interventions that will ultimately lead to better overall care for cancer patients.
Collapse
Affiliation(s)
- Katherine E. Pendleton
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, United States
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
| | - Karen Wang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, United States
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
- Department of BioSciences, Rice University, Houston, TX, United States
| | - Gloria V. Echeverria
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, United States
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
| |
Collapse
|
|
25
|
Buczyńska A, Sidorkiewicz I, Kościuszko M, Adamska A, Siewko K, Dzięcioł J, Szumowski P, Myśliwiec J, Szelachowska M, Popławska-Kita A, Krętowski A. Clinical significance of oxidative stress markers as angioinvasion and metastasis indicators in papillary thyroid cancer. Sci Rep 2023; 13:13711. [PMID: 37608150 PMCID: PMC10444813 DOI: 10.1038/s41598-023-40898-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 08/17/2023] [Indexed: 08/24/2023] Open
Abstract
Angioinvasion remains the important prognostic feature in papillary thyroid cancer (PTC) patients. Literature data indicates several markers that may be associated with oxidative stress and/or angioinvasion. Therefore, we assessed the utility of selected parameters in angioinvasion and metastasis screening in serum of PTC patients. Serum antioxidant capacity (TAC) and sirtuin 3 (SIRT3) levels were decreased (all p < 0.05) and both DNA/RNA oxidative stress damage products (DNA/RNA OSDP) and malondialdehyde (MDA) levels were increased in PTC patients with angioinvasion and metastasis (study group) when compared with PTC patients without these features (all p < 0.01). The highest screening utility in differentiation between angioinvasion and metastasis presence and absence in PTC patients was presented for DNA/RNA OSDP (AUC = 0.71), SIRT3 (AUC = 0.70), and TAC (AUC = 0.67) (all p < 0.05). Our study suggests that peripheral concentration of oxidative stress markers could be useful as angioinvasion and metastasis indicator in PTC patients.
Collapse
Affiliation(s)
- Angelika Buczyńska
- Clinical Research Centre, Medical University of Bialystok, 15-276, Białystok, Poland.
| | - Iwona Sidorkiewicz
- Clinical Research Support Centre, Medical University of Bialystok, Ul. M. Skłodowskiej-Curie 24a, 15-276, Białystok, Poland
| | - Maria Kościuszko
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-276, Białystok, Poland
| | - Agnieszka Adamska
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-276, Białystok, Poland
| | - Katarzyna Siewko
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-276, Białystok, Poland
| | - Janusz Dzięcioł
- Department of Human Anatomy, Medical University of Bialystok, 15-276, Białystok, Poland
| | - Piotr Szumowski
- Nuclear Medicine, Medical University of Bialystok, 15-276, Białystok, Poland
| | - Janusz Myśliwiec
- Nuclear Medicine, Medical University of Bialystok, 15-276, Białystok, Poland
| | - Małgorzata Szelachowska
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-276, Białystok, Poland
| | - Anna Popławska-Kita
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-276, Białystok, Poland.
| | - Adam Krętowski
- Clinical Research Centre, Medical University of Bialystok, 15-276, Białystok, Poland
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-276, Białystok, Poland
| |
Collapse
|
|
26
|
Vardar Acar N, Özgül RK. The bridge between cell survival and cell death: reactive oxygen species-mediated cellular stress. EXCLI JOURNAL 2023; 22:520-555. [PMID: 37534225 PMCID: PMC10390897 DOI: 10.17179/excli2023-6221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 06/15/2023] [Indexed: 08/04/2023]
Abstract
As a requirement of aerobic metabolism, regulation of redox homeostasis is indispensable for the continuity of living homeostasis and life. Since the stability of the redox state is necessary for the maintenance of the biological functions of the cells, the balance between the pro-oxidants, especially ROS and the antioxidant capacity is kept in balance in the cells through antioxidant defense systems. The pleiotropic transcription factor, Nrf2, is the master regulator of the antioxidant defense system. Disruption of redox homeostasis leads to oxidative and reductive stress, bringing about multiple pathophysiological conditions. Oxidative stress characterized by high ROS levels causes oxidative damage to biomolecules and cell death, while reductive stress characterized by low ROS levels disrupt physiological cell functions. The fact that ROS, which were initially attributed as harmful products of aerobic metabolism, at the same time function as signal molecules at non-toxic levels and play a role in the adaptive response called mithormesis points out that ROS have a dose-dependent effect on cell fate determination. See also Figure 1(Fig. 1).
Collapse
Affiliation(s)
- Nese Vardar Acar
- Department of Pediatric Metabolism, Institute of Child Health, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Riza Köksal Özgül
- Department of Pediatric Metabolism, Institute of Child Health, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| |
Collapse
|
|
27
|
Casas-Benito A, Martínez-Herrero S, Martínez A. Succinate-Directed Approaches for Warburg Effect-Targeted Cancer Management, an Alternative to Current Treatments? Cancers (Basel) 2023; 15:2862. [PMID: 37345199 DOI: 10.3390/cancers15102862] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/22/2023] [Accepted: 05/08/2023] [Indexed: 06/23/2023] Open
Abstract
Approximately a century ago, Otto Warburg discovered that cancer cells use a fermentative rather than oxidative metabolism even though the former is more inefficient in terms of energy production per molecule of glucose. Cancer cells increase the use of this fermentative metabolism even in the presence of oxygen, and this process is called aerobic glycolysis or the Warburg effect. This alternative metabolism is mainly characterized by higher glycolytic rates, which allow cancer cells to obtain higher amounts of total ATP, and the production of lactate, but there are also an activation of protumoral signaling pathways and the generation of molecules that favor cancer progression. One of these molecules is succinate, a Krebs cycle intermediate whose concentration is increased in cancer and which is considered an oncometabolite. Several protumoral actions have been associated to succinate and its role in several cancer types has been already described. Despite playing a major role in metabolism and cancer, so far, the potential of succinate as a target in cancer prevention and treatment has remained mostly unexplored, as most previous Warburg-directed anticancer strategies have focused on other intermediates. In this review, we aim to summarize succinate's protumoral functions and discuss the use of succinate expression regulators as a potential cancer therapy strategy.
Collapse
Affiliation(s)
- Adrian Casas-Benito
- Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), 26006 Logroño, Spain
| | - Sonia Martínez-Herrero
- Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), 26006 Logroño, Spain
| | - Alfredo Martínez
- Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), 26006 Logroño, Spain
| |
Collapse
|
|
28
|
Park JW, Tyl MD, Cristea IM. Orchestration of Mitochondrial Function and Remodeling by Post-Translational Modifications Provide Insight into Mechanisms of Viral Infection. Biomolecules 2023; 13:biom13050869. [PMID: 37238738 DOI: 10.3390/biom13050869] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/17/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
The regulation of mitochondria structure and function is at the core of numerous viral infections. Acting in support of the host or of virus replication, mitochondria regulation facilitates control of energy metabolism, apoptosis, and immune signaling. Accumulating studies have pointed to post-translational modification (PTM) of mitochondrial proteins as a critical component of such regulatory mechanisms. Mitochondrial PTMs have been implicated in the pathology of several diseases and emerging evidence is starting to highlight essential roles in the context of viral infections. Here, we provide an overview of the growing arsenal of PTMs decorating mitochondrial proteins and their possible contribution to the infection-induced modulation of bioenergetics, apoptosis, and immune responses. We further consider links between PTM changes and mitochondrial structure remodeling, as well as the enzymatic and non-enzymatic mechanisms underlying mitochondrial PTM regulation. Finally, we highlight some of the methods, including mass spectrometry-based analyses, available for the identification, prioritization, and mechanistic interrogation of PTMs.
Collapse
Affiliation(s)
- Ji Woo Park
- Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA
| | - Matthew D Tyl
- Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA
| | - Ileana M Cristea
- Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA
| |
Collapse
|
|
29
|
Jin J, Bai L, Wang D, Ding W, Cao Z, Yan P, Li Y, Xi L, Wang Y, Zheng X, Wei H, Ding C, Wang Y. SIRT3-dependent delactylation of cyclin E2 prevents hepatocellular carcinoma growth. EMBO Rep 2023; 24:e56052. [PMID: 36896611 PMCID: PMC10157311 DOI: 10.15252/embr.202256052] [Citation(s) in RCA: 85] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 01/30/2023] [Accepted: 02/20/2023] [Indexed: 03/11/2023] Open
Abstract
Lysine lactylation (Kla) is a recently discovered histone mark derived from metabolic lactate. The NAD+ -dependent deacetylase SIRT3, which can also catalyze removal of the lactyl moiety from lysine, is expressed at low levels in hepatocellular carcinoma (HCC) and has been suggested to be an HCC tumor suppressor. Here we report that SIRT3 can delactylate non-histone proteins and suppress HCC development. Using SILAC-based quantitative proteomics, we identify cyclin E2 (CCNE2) as one of the lactylated substrates of SIRT3 in HCC cells. Furthermore, our crystallographic study elucidates the mechanism of CCNE2 K348la delactylation by SIRT3. Our results further suggest that lactylated CCNE2 promotes HCC cell growth, while SIRT3 activation by Honokiol induces HCC cell apoptosis and prevents HCC outgrowth in vivo by regulating Kla levels of CCNE2. Together, our results establish a physiological function of SIRT3 as a delactylase that is important for suppressing HCC, and our structural data could be useful for the future design of activators.
Collapse
Affiliation(s)
- Jing Jin
- Division of Life Sciences and Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHeifeiChina
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical CenterUniversity of Science and Technology of ChinaHefeiChina
| | - Lin Bai
- State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Human Phenome Institute, School of Life Sciences, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Dongyao Wang
- Division of Life Sciences and Medicine, Department of Hematology, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHefeiChina
| | - Wei Ding
- Beijing National Laboratory for Condensed Matter Physics, Institute of PhysicsChinese Academy of SciencesBeijingChina
| | - Zhuoxian Cao
- Division of Life Sciences and Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHeifeiChina
| | - Peidong Yan
- Division of Life Sciences and Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHeifeiChina
| | - Yunjia Li
- Division of Life Sciences and Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHeifeiChina
| | - Lulu Xi
- Division of Life Sciences and Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHeifeiChina
| | - Yuxin Wang
- Division of Life Sciences and Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHeifeiChina
| | - Xiaohu Zheng
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical CenterUniversity of Science and Technology of ChinaHefeiChina
| | - Haiming Wei
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical CenterUniversity of Science and Technology of ChinaHefeiChina
| | - Chen Ding
- State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Human Phenome Institute, School of Life Sciences, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Yi Wang
- Division of Life Sciences and Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHeifeiChina
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical CenterUniversity of Science and Technology of ChinaHefeiChina
| |
Collapse
|
|
30
|
Islam S, Mukherjee C. Molecular regulation of hypoxia through the lenses of noncoding RNAs and epitranscriptome. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1750. [PMID: 35785444 DOI: 10.1002/wrna.1750] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 05/27/2022] [Accepted: 06/06/2022] [Indexed: 11/09/2022]
Abstract
Cells maintain homeostasis in response to environmental stress through specific cell stress responses. Hypoxic stress, well known to be associated with diverse solid tumors, is one of the main reasons for cancer-related mortality. Although cells can balance themselves well during hypoxic stress, the underlying molecular mechanisms are not well understood. The enhanced appreciation of diverse roles played by noncoding transcriptome and epigenome in recent years has brought to light the involvement of noncoding RNAs and epigenetic modifiers in hypoxic regulation. The emergence of techniques like deep sequencing has facilitated the identification of large numbers of long noncoding RNAs (lncRNAs) that are differentially regulated in various cancers. Similarly, proteomic studies have identified diverse epigenetic modifiers such as HATs, HDACs, DNMTs, polycomb groups of proteins, and their possible roles in the regulation of hypoxia. The crosstalk between lncRNAs and epigenetic modifiers play a pivotal role in hypoxia-induced cancer initiation and progression. Besides the lncRNAs, several other noncoding RNAs like circular RNAs, miRNAs, and so forth are also expressed during hypoxic conditions. Hypoxia has a profound effect on the expression of noncoding RNAs and epigenetic modifiers. Conversely, noncoding RNAs/epigenetic modifies can regulate the hypoxia signaling axis by modulating the stability of the hypoxia-inducible factors (HIFs). The focus of this review is to illustrate the molecular orchestration underlying hypoxia biology, especially in cancers, which can help in identifying promising therapeutic targets in hypoxia-induced cancers. This article is categorized under: RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Disease RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry.
Collapse
Affiliation(s)
- Safirul Islam
- Institute of Health Sciences (erstwhile School of Biotechnology), Presidency University, Kolkata, India
| | - Chandrama Mukherjee
- Institute of Health Sciences (erstwhile School of Biotechnology), Presidency University, Kolkata, India
| |
Collapse
|
|
31
|
Ma S, Ge Y, Xiong Z, Wang Y, Li L, Chao Z, Li B, Zhang J, Ma S, Xiao J, Liu B, Wang Z. A novel gene signature related to oxidative stress predicts the prognosis in clear cell renal cell carcinoma. PeerJ 2023; 11:e14784. [PMID: 36785707 PMCID: PMC9921988 DOI: 10.7717/peerj.14784] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 01/03/2023] [Indexed: 02/10/2023] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is considered to be related to the worse prognosis, which might in part be attributed to the early recurrence and metastasis, compared with other type of kidney cancer. Oxidative stress refers to an imbalance between production of oxidants and antioxidant defense. Accumulative studies have indicated that oxidative stress genes contribute to the tumor invasion, metastasis and drug sensitivity. However, the biological functions of oxidative stress genes in ccRCC remain largely unknown. In this study, we identified 1,399 oxidative stress genes from GeneCards with a relevance score ≥7. Data for analysis were accessed from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) database, and were utilized as training set and validation set respectively. Univariate Cox analysis, least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox were employed to construct a prognostic signature in ccRCC. Finally, a prognostic signature including four different oxidative stress genes was constructed from 1,399 genes, and its predictive performance was verified through Kaplan-Meier survival analysis and the receiver operating characteristic (ROC) curve. Interestingly, we found that there was significant correlation between the expression of oxidative stress genes and the immune infiltration and the sensitivity of tumor cells to chemotherapeutics. Moreover, the highest hazard ratio gene urocortin (UCN) was chosen for further study; some necessary vitro experiments proved that the UCN could promote the ability of ccRCC proliferation and migration and contribute to the degree of oxidative stress. In conclusion, it was promising to predict the prognosis of ccRCC through the four oxidative stress genes signature. UCN played oncogenic roles in ccRCC by influencing proliferation and oxidative stress pathway, which was expected to be the novel therapeutic target for ccRCC.
Collapse
Affiliation(s)
- Sheng Ma
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yue Ge
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zezhong Xiong
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yanan Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Le Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zheng Chao
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Beining Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Junbiao Zhang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Siquan Ma
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jun Xiao
- Department of Thyroid and Breast Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bo Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhihua Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| |
Collapse
|
|
32
|
Wu L, Yan X, Sun R, Ma Y, Yao W, Gao B, Zhang Q, You J, Wang H, Han Q, Sun X. Sirt3 restricts tumor initiation via promoting LONP1 deacetylation and K63 ubiquitination. J Transl Med 2023; 21:81. [PMID: 36739437 PMCID: PMC9899405 DOI: 10.1186/s12967-023-03925-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 01/25/2023] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sirtuin 3 (Sirt3) is a controversial regulator of carcinogenesis. It residents in the mitochondria and gradually decays during aging. In this study, we tried to investigate the role of Sirt3 in carcinogenesis and to explore its involvement in metabolic alteration. METHODS We generated conditional intestinal epithelium Sirt3-knockout mice by crossing ApcMin/+; Villin-Cre with Sirt3fl/fl (AVS) mice. The deacetylation site of Lon protease-1 (LONP1) was identified with Mass spectrometry. The metabolic flux phenotype was determined by Seahorse bioanalyzer. RESULTS We found that intestinal epithelial cell-specific ablation of Sirt3 promotes primary tumor growth via stabilizing mitochondrial LONP1. Notably, we newly identified that Sirt3 deacetylates human oncogene LONP1 at N terminal residue lysine 145 (K145). The LONP1 hyperacetylation-mutant K145Q enhances oxidative phosphorylation to accelerate tumor growth, whereas the deacetylation-mutant K145R produces calorie-restriction like phenotype to restrain tumorigenesis. Sirt3 deacetylates LONP1 at K145 and subsequently facilitates the ESCRT0 complex sorting and K63-ubiquitination that resulted in the degradation of LONP1. Our results sustain the notion that Sirt3 is a tumor-suppressor to maintain the appropriate ubiquitination and degradation of oncogene LONP1. CONCLUSION Sirt3 represents a targetable metabolic checkpoint of oncogenesis, which produces energy restriction effects via maintaining LONP1 K145 deacetylation and subsequent K63 ubiquitination.
Collapse
Affiliation(s)
- Liyi Wu
- grid.284723.80000 0000 8877 7471The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515 Guangdong China
| | - Xinyi Yan
- grid.284723.80000 0000 8877 7471The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515 Guangdong China
| | - Ruibo Sun
- grid.284723.80000 0000 8877 7471The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515 Guangdong China
| | - Ye Ma
- grid.284723.80000 0000 8877 7471The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515 Guangdong China
| | - Wanyu Yao
- grid.284723.80000 0000 8877 7471The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515 Guangdong China
| | - Baogui Gao
- grid.284723.80000 0000 8877 7471The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515 Guangdong China
| | - Qingyuan Zhang
- grid.284723.80000 0000 8877 7471The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515 Guangdong China
| | - Junxiong You
- grid.284723.80000 0000 8877 7471The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515 Guangdong China
| | - Hao Wang
- grid.284723.80000 0000 8877 7471The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515 Guangdong China
| | - Qinrui Han
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China.
| | - Xuegang Sun
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China. .,Department of Traditional Chinese Medicine, Zhujing Hospital, Southern Medical University, Guangzhou, 510260, Guangdong, China.
| |
Collapse
|
|
33
|
Clemente-Suárez VJ, Martín-Rodríguez A, Redondo-Flórez L, Ruisoto P, Navarro-Jiménez E, Ramos-Campo DJ, Tornero-Aguilera JF. Metabolic Health, Mitochondrial Fitness, Physical Activity, and Cancer. Cancers (Basel) 2023; 15:814. [PMID: 36765772 PMCID: PMC9913323 DOI: 10.3390/cancers15030814] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 01/26/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
Cancer continues to be a significant global health issue. Traditional genetic-based approaches to understanding and treating cancer have had limited success. Researchers are increasingly exploring the impact of the environment, specifically inflammation and metabolism, on cancer development. Examining the role of mitochondria in this context is crucial for understanding the connections between metabolic health, physical activity, and cancer. This study aimed to review the literature on this topic through a comprehensive narrative review of various databases including MedLine (PubMed), Cochrane (Wiley), Embase, PsychINFO, and CinAhl. The review highlighted the importance of mitochondrial function in overall health and in regulating key events in cancer development, such as apoptosis. The concept of "mitochondrial fitness" emphasizes the crucial role of mitochondria in cell metabolism, particularly their oxidative functions, and how proper function can prevent replication errors and regulate apoptosis. Engaging in high-energy-demanding movement, such as exercise, is a powerful intervention for improving mitochondrial function and increasing resistance to environmental stressors. These findings support the significance of considering the role of the environment, specifically inflammation and metabolism, in cancer development and treatment. Further research is required to fully understand the mechanisms by which physical activity improves mitochondrial function and potentially reduces the risk of cancer.
Collapse
Affiliation(s)
| | | | - Laura Redondo-Flórez
- Department of Health Sciences, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, C/Tajo s/n Villaviciosa de Odón, 28670 Madrid, Spain
| | - Pablo Ruisoto
- Department of Health Sciences, Public University of Navarre, 31006 Navarre, Spain
| | | | | | | |
Collapse
|
|
34
|
Sharma A, Mahur P, Muthukumaran J, Singh AK, Jain M. Shedding light on structure, function and regulation of human sirtuins: a comprehensive review. 3 Biotech 2023; 13:29. [PMID: 36597461 PMCID: PMC9805487 DOI: 10.1007/s13205-022-03455-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 12/25/2022] [Indexed: 01/01/2023] Open
Abstract
Sirtuins play an important role in signalling pathways associated with various metabolic regulations. They possess mono-ADP-ribosyltransferase or deacylase activity like demalonylase, deacetylase, depalmitoylase, demyristoylase and desuccinylase activity. Sirtuins are histone deacetylases which depends upon nicotinamide adenine dinucleotide (NAD) that deacetylate lysine residues. There are a total of seven human sirtuins that have been identified namely, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7. The subcellular location of mammalian sirtuins, SIRT1, SIRT6, and SIRT7 are in the nucleus; SIRT3, SIRT4, and SIRT5 are in mitochondria, and SIRT2 is in cytoplasm. Structurally sirtuins contains a N-terminal, a C-terminal and a Zn+ binding domain. The sirtuin family has been found to be crucial for maintaining lipid and glucose homeostasis, and also for regulating insulin secretion and sensitivity, DNA repair pathways, neurogenesis, inflammation, and ageing. Based on the literature, sirtuins are overexpressed and play an important role in tumorigenicity in various types of cancer such as non-small cell lung cancer, colorectal cancer, etc. In this review, we have discussed about the different types of human sirtuins along with their structural and functional features. We have also discussed about the various natural and synthetic regulators of sirtuin activities like resveratrol. Our overall study shows that the correct regulation of sirtuins can be a good target for preventing and treating various diseases for improving the human lifespan. To investigate the true therapeutic potential of sirtuin proteins and their efficacy in a variety of pathological diseases, a better knowledge of the link between the structure and function of sirtuin proteins would be necessary.
Collapse
Affiliation(s)
- Abhishek Sharma
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
| | - Pragati Mahur
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
| | - Jayaraman Muthukumaran
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
| | - Amit Kumar Singh
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
| | - Monika Jain
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
| |
Collapse
|
|
35
|
Zhou B, Lei JH, Wang Q, Qu TF, Cha LC, Zhan HX, Liu SL, Hu X, Sun CD, Guo WD, Qiu FB, Cao JY. Cancer-associated fibroblast-secreted miR-421 promotes pancreatic cancer by regulating the SIRT3/H3K9Ac/HIF-1α axis. Kaohsiung J Med Sci 2022; 38:1080-1092. [PMID: 36200682 DOI: 10.1002/kjm2.12590] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 07/18/2022] [Accepted: 08/09/2022] [Indexed: 11/10/2022] Open
Abstract
This study was designed to explore the effects of exosomal miR-421 secreted by cancer-associated fibroblasts (CAFs) on pancreatic cancer (PC) progression and the mechanisms involved. CAFs and exosomes (exos) were isolated and identified. PC cells were treated with CAF-derived exos (CAF-exos). Western blotting and quantitative polymerase chain reaction (qPCR) were used to measure miR-421, sirtuin-3 (SIRT3), and hypoxia duciblefactors-1 alpha (HIF-1α) levels. Cell counting kit-8 (CCK-8), wound-healing, and transwell migration assays were used to measure proliferation, migration, and invasion abilities of the cells. Dual-luciferase assay and RNA immunoprecipitation (RIP) experiment analyzed the relationship between miR-421 and SIRT3. Chromatin immunoprecipitation (f)-verified H3K9Ac enrichment in the HIF-1α promoter region. In vivo tumorigenesis experiments were performed to further explore the effects of exosomal miR-421 from CAFs on PC. CAFs and exos were successfully isolated. CAF-exo-treated PC cells highly expressed miR-421 and had increased cell proliferation, migration, and invasion abilities. Knocking down miR-421 increased the expression of SIRT3. SIRT3 is a target of miR-421, and inhibiting the expression of SIRT3 reversed the negative effects of miR-421 knockdown on PC cell. Knocking down miR-421 in CAF-exo inhibited the expression of HIF-1α in PC cells. Moreover, SIRT3-mediated HIF-1α expression by regulating H3K9Ac. HIF-1α overexpression reversed the inhibiting effects of SIRT3 overexpression on PC progression and counteracted the inhibiting effects of miR-421 knockdown on glycolysis. Moreover, in vivo tumorigenesis experiments showed that knocking down miR-421 attenuated CAF-exo induced tumor growth. Exosomal miR-421 from CAFs promoted PC progression by regulating the SIRT3/H3K9Ac/HIF-1α axis. This study provided insights into the molecular mechanism of PC.
Collapse
Affiliation(s)
- Bin Zhou
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Jing-Hao Lei
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Qiang Wang
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Teng-Fei Qu
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Li-Chao Cha
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Han-Xiang Zhan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, People's Republic of China
| | - Shang-Long Liu
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Xiao Hu
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Chuan-Dong Sun
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Wei-Dong Guo
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Fa-Bo Qiu
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Jing-Yu Cao
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| |
Collapse
|
|
36
|
Downregulation of SIRT3 Aggravates Lung Ischemia Reperfusion Injury by Increasing Mitochondrial Fission and Oxidative Stress through HIF-1α-Dependent Mechanisms. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9041914. [PMID: 36211825 PMCID: PMC9537006 DOI: 10.1155/2022/9041914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 04/11/2022] [Accepted: 05/27/2022] [Indexed: 12/06/2022]
Abstract
Lung ischemia-reperfusion injury (LIRI) is a severe multifaceted pathological condition that can lead to poor patient outcome where oxidative stress and the resulting inflammatory response can trigger and exacerbate tissue damage in LIRI patients. Sirtuin3 (SIRT3), a member of the sirtuin family, protects against oxidative stress-related diseases. However, it remains unclear if and how SIRT3 alleviates lung injury induced by ischemia/reperfusion (I/R). Our previous study showed that lung tissue structures were severely damaged at 6 h after lung I/R in mice, however, repair of the injured lung tissue was significant at 24 h. In this study, we found that both SIRT3 mRNA and protein levels were markedly increased at 24 h after lung I/R in vivo. Meanwhile, inhibition of SIRT3 aggravated lung injury and inflammation, augmented mitochondrial fission and oxidative stress and increased Hypoxia-inducible factor-1α (HIF-1α) expression in vivo. The results suggest that SIRT3 may be an upstream regulator of HIF-1α expression. Knockdown of SIRT3 resulted in excessive mitochondrial fission and increased oxidative stress in vitro, and we found that knocking down the expression of HIF-1α alleviated these changes. This suggests that the SIRT3-HIF-1α signaling pathway is involved in regulating mitochondrial function and oxidative stress. Furthermore, inhibition of dynamin-related protein 1 (Drp-1) by the inhibitor of mitophagy, Mdivi-1, blocked mitochondrial fission and alleviated oxidative stress in vitro. Taken together, our results demonstrated that downregulation of SIRT3 aggravates LIRI by increasing mitochondrial fission and oxidative stress. Activation of SIRT3 inhibits mitochondrial fission and this mechanism may serve as a new therapeutic strategy to treat LIRI.
Collapse
|
|
37
|
Azzam HN, El-Derany MO, Wahdan SA, Faheim RM, Helal GK, El-Demerdash E. Metabolic/hypoxial axis predicts tamoxifen resistance in breast cancer. Sci Rep 2022; 12:16118. [PMID: 36167713 PMCID: PMC9515205 DOI: 10.1038/s41598-022-19977-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 09/07/2022] [Indexed: 11/25/2022] Open
Abstract
We sought in our cross-sectional study to investigate the role of metabolic/hypoxial axis in the development of tamoxifen (TMX) resistance in BC patients. Quantification of plasma LncRNA Taurine upregulated-1 (TUG-1), miRNA 186-5p (miR-186), serum Sirtuin-3 (SIRT3), Peroxisome Proliferator Activator Receptor alpha (PPAR-1 α) and Hypoxia Inducible Factor-1 (HIF-1α) was done in a cohort of patients divided into TMX-sensitive and TMX-resistant candidates. Multiple logistic regression and Receiver Operating Characteristic curve were developed for significant predictors. Plasma TUG-1 and miR-186 were significantly elevated in TMX resistant patients. Serum proteins SIRT3, PPAR-1 α and HIF-1α were deficient in TMX resistant patients compared to TMX sensitive patients, respectively. miR-186 was associated with respiratory symptoms, while, HIF-1α was associated with metastases in TMX resistant patients. Strong correlations were found between all parameters. A predictive model was constructed with TUG-1 and HIF-1α to estimate TMX resistance in BC patients with 88.3% sensitivity and 91.6% specificity. Hypoxia and metabolic dysregulations play important role in the development of TMX resistance in BC patients. Correlation between hypoxia, carcinogenesis and patient’s mortality have led to more aggressive phenotypes, increased risk of metastasis and resistance to TMX.
Collapse
Affiliation(s)
- Hany N Azzam
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt
| | - Marwa O El-Derany
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Sara A Wahdan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Reham M Faheim
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Gouda K Helal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt
| | - Ebtehal El-Demerdash
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
| |
Collapse
|
|
38
|
Role of Carbon Monoxide in Oxidative Stress-Induced Senescence in Human Bronchial Epithelium. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5199572. [PMID: 36193088 PMCID: PMC9526622 DOI: 10.1155/2022/5199572] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 08/28/2022] [Indexed: 11/17/2022]
Abstract
Prolonged or excessive stimulation from inhaled toxins may cause oxidative stress and DNA damage that can lead to stress-induced senescence in epithelial cells, which can contribute to several airway diseases. Mounting evidence has shown carbon monoxide (CO) confers cytoprotective effects. We investigated the effects of CO on oxidative stress-induced senescence in human airway epithelium and elucidated the underlying molecular mechanisms. Here, CO pretreatment reduced H2O2-mediated increases in total reactive oxygen species (ROS) production and mitochondrial superoxide in a human bronchial epithelial cell line (BEAS-2B). H2O2 treatment triggered a premature senescence-like phenotype with enlarged and flattened cell morphology accompanied by increased SA-β-gal activity, cell cycle arrest in G0/G1, reduced cell viability, and increased transcription of senescence-associated secretory phenotype (SASP) genes. Additionally, exposure to H2O2 increased protein levels of cellular senescence markers (p53 and p21), reduced Sirtuin 3 (SIRT3) and manganese superoxide dismutase (MnSOD) levels, and increased p53 K382 acetylation. These H2O2-mediated effects were attenuated by pretreatment with a CO-containing solution. SIRT3 silencing induced mitochondrial superoxide production and triggered a senescence-like phenotype, whereas overexpression decreased mitochondrial superoxide production and alleviated the senescence-like phenotype. Air-liquid interface (ALI) culture of primary human bronchial cells, which becomes a fully differentiated pseudostratified mucociliary epithelium, was used as a model. We found that apical and basolateral exposure to H2O2 induced a vacuolated structure that impaired the integrity of ALI cultures, increased goblet cell numbers, decreased SCGB1A1+ club cell numbers, increased p21 protein levels, and increased SASP gene transcription, consistent with our observations in BEAS-2B cells. These effects were attenuated in the apical presence of a CO-containing solution. In summary, we revealed that CO has a pivotal role in epithelial senescence by regulating ROS production via the SIRT3/MnSOD/p53/p21 pathway. This may have important implications in the prevention and treatment of age-associated respiratory pathologies.
Collapse
|
|
39
|
Mitochondrial Regulation of the Hypoxia-Inducible Factor in the Development of Pulmonary Hypertension. J Clin Med 2022; 11:jcm11175219. [PMID: 36079149 PMCID: PMC9457092 DOI: 10.3390/jcm11175219] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 08/27/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022] Open
Abstract
Pulmonary hypertension (PH) is a severe progressive lung disorder characterized by pulmonary vasoconstriction and vascular remodeling, culminating in right-sided heart failure and increased mortality. Data from animal models and human subjects demonstrated that hypoxia-inducible factor (HIF)-related signaling is essential in the progression of PH. This review summarizes the regulatory pathways and mechanisms of HIF-mediated signaling, emphasizing the role of mitochondria in HIF regulation and PH pathogenesis. We also try to determine the potential to therapeutically target the components of the HIF system for the management of PH.
Collapse
|
|
40
|
Dzhalilova DS, Makarova OV. The Role of Hypoxia-Inducible Factor in the Mechanisms of Aging. BIOCHEMISTRY. BIOKHIMIIA 2022; 87:995-1014. [PMID: 36180993 DOI: 10.1134/s0006297922090115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/17/2022] [Accepted: 08/17/2022] [Indexed: 06/16/2023]
Abstract
Aging is accompanied by a reduction in the oxygen delivery to all organs and tissues and decrease in the oxygen partial pressure in them, resulting in the development of hypoxia. The lack of oxygen activates cell signaling pathway mediated by the hypoxia-inducible transcription factor (HIF), which exists in three isoforms - HIF-1, HIF-2, and HIF-3. HIF regulates expression of several thousand genes and is a potential target for the development of new drugs for the treatment of many diseases, including those associated with age. Human organism and organisms of laboratory animals differ in their tolerance to hypoxia and expression of HIF and HIF-dependent genes, which may contribute to the development of inflammatory, tumor, and cardiovascular diseases. Currently, the data on changes in the HIF expression with age are contradictory, which is mostly due to the fact that such studies are conducted in different age groups, cell types, and model organisms, as well as under different hypoxic conditions and mainly in vitro. Furthermore, the observed discrepancies can be due to the individual tolerance of the studied organisms to hypoxia, which is typically not taken into account. Therefore, the purpose of this review was to analyze the published data on the connection between the mechanisms of aging, basal tolerance to hypoxia, and changes in the level of HIF expression with age. Here, we summarized the data on the age-related changes in the hypoxia tolerance, HIF expression and the role of HIF in aging, which is associated with its involvement in the molecular pathways mediated by insulin and IGF-1 (IIS), sirtuins (SIRTs), and mTOR. HIF-1 interacts with many components of the IIS pathway, in particular with FOXO, the activation of which reduces production of reactive oxygen species (ROS) and increases hypoxia tolerance. Under hypoxic conditions, FOXO is activated via both HIF-dependent and HIF-independent pathways, which contributes to a decrease in the ROS levels. The activity of HIF-1 is regulated by all members of the sirtuin family, except SIRT5, while the mechanisms of SIRT interaction with HIF-2 and HIF-3 are poorly understood. The connection between HIF and mTOR and its inhibitor, AMPK, has been identified, but its exact mechanism has yet to be studied. Understanding the role of HIF and hypoxia in aging and pathogenesis of age-associated diseases is essential for the development of new approaches to the personalized therapy of these diseases, and requires further research.
Collapse
Affiliation(s)
- Dzhuliia Sh Dzhalilova
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Centre of Surgery, Moscow, 117418, Russia.
| | - Olga V Makarova
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Centre of Surgery, Moscow, 117418, Russia
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
| |
Collapse
|
|
41
|
Abbotto E, Scarano N, Piacente F, Millo E, Cichero E, Bruzzone S. Virtual Screening in the Identification of Sirtuins’ Activity Modulators. Molecules 2022; 27:molecules27175641. [PMID: 36080416 PMCID: PMC9457788 DOI: 10.3390/molecules27175641] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 11/23/2022] Open
Abstract
Sirtuins are NAD+-dependent deac(et)ylases with different subcellular localization. The sirtuins’ family is composed of seven members, named SIRT-1 to SIRT-7. Their substrates include histones and also an increasing number of different proteins. Sirtuins regulate a wide range of different processes, ranging from transcription to metabolism to genome stability. Thus, their dysregulation has been related to the pathogenesis of different diseases. In this review, we discussed the pharmacological approaches based on sirtuins’ modulators (both inhibitors and activators) that have been attempted in in vitro and/or in in vivo experimental settings, to highlight the therapeutic potential of targeting one/more specific sirtuin isoform(s) in cancer, neurodegenerative disorders and type 2 diabetes. Extensive research has already been performed to identify SIRT-1 and -2 modulators, while compounds targeting the other sirtuins have been less studied so far. Beside sections dedicated to each sirtuin, in the present review we also included sections dedicated to pan-sirtuins’ and to parasitic sirtuins’ modulators. A special focus is dedicated to the sirtuins’ modulators identified by the use of virtual screening.
Collapse
Affiliation(s)
- Elena Abbotto
- Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy
| | - Naomi Scarano
- Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
| | - Francesco Piacente
- Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy
| | - Enrico Millo
- Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy
| | - Elena Cichero
- Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
| | - Santina Bruzzone
- Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy
- Correspondence:
| |
Collapse
|
|
42
|
Faienza F, Rasola A, Filomeni G. Nitric oxide-based regulation of metabolism: Hints from TRAP1 and SIRT3 crosstalk. Front Mol Biosci 2022; 9:942729. [PMID: 35959462 PMCID: PMC9360569 DOI: 10.3389/fmolb.2022.942729] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/06/2022] [Indexed: 11/13/2022] Open
Affiliation(s)
- Fiorella Faienza
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Andrea Rasola
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Giuseppe Filomeni
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- Redox Biology, Danish Cancer Society Research Center, Copenhagen, Denmark
- Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
43
|
Yapryntseva MA, Maximchik PV, Zhivotovsky B, Gogvadze V. Mitochondrial sirtuin 3 and various cell death modalities. Front Cell Dev Biol 2022; 10:947357. [PMID: 35938164 PMCID: PMC9354933 DOI: 10.3389/fcell.2022.947357] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 07/05/2022] [Indexed: 11/13/2022] Open
Abstract
Sirtuin 3, a member of the mammalian sirtuin family of proteins, is involved in the regulation of multiple processes in cells. It is a major mitochondrial NAD+-dependent deacetylase with a broad range of functions, such as regulation of oxidative stress, reprogramming of tumor cell energy pathways, and metabolic homeostasis. One of the intriguing functions of sirtuin 3 is the regulation of mitochondrial outer membrane permeabilization, a key step in apoptosis initiation/progression. Moreover, sirtuin 3 is involved in the execution of various cell death modalities, which makes sirtuin 3 a possible regulator of crosstalk between them. This review is focused on the role of sirtuin 3 as a target for tumor cell elimination and how mitochondria and reactive oxygen species (ROS) are implicated in this process.
Collapse
Affiliation(s)
| | - Polina V. Maximchik
- Faculty of Basic Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Boris Zhivotovsky
- Faculty of Basic Medicine, Lomonosov Moscow State University, Moscow, Russia
- Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden
| | - Vladimir Gogvadze
- Faculty of Basic Medicine, Lomonosov Moscow State University, Moscow, Russia
- Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden
- *Correspondence: Vladimir Gogvadze,
| |
Collapse
|
|
44
|
Singh V, Singh R, Kushwaha R, Verma SP, Tripathi AK, Mahdi AA. The Molecular Role of HIF1α Is Elucidated in Chronic Myeloid Leukemia. Front Oncol 2022; 12:912942. [PMID: 35847841 PMCID: PMC9279726 DOI: 10.3389/fonc.2022.912942] [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: 04/05/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic myeloid leukemia (CML) is potentially fatal blood cancer, but there is an unmet need to discover novel molecular biomarkers. The hypothesis of this study aimed to elucidate the relationship of HIF1α with the redox system, Krebs cycles, notch1, and other regulatory proteins to better understand the pathophysiology and clinical relevance in chronic myeloid leukemia (CML) patients, as the molecular mechanism of this axis is still not clear. This study included CML patient samples (n = 60; 60: blood; 10: bone marrow tissues) and compared them with healthy controls (n = 20; blood). Clinical diagnosis confirmed on bone marrow aspiration, marrow trephine biopsy, and BCR/ABL1 translocation. Cases were subclassified into chronic, accelerated, and blast crises as per WHO guidelines. Molecular experiments included redox parameters, DNA fragmentation, Krebs cycle metabolites, and gene expression by RT-PCR/Western blot/LC-MS, PPI (STRING), Pearson correlation, and ROC curve analysis. Here, our findings show that p210/p190BCR/ABL1 translocation is common in all blast crisis phases of CML. Redox factor/Krebs oncometabolite concentrations were high, leading to upregulation and stabilization of HIF1α. HIF1α leads to the pathogenesis in CML cells by upregulating their downstream genes (Notch 2/4/Ikaros/SIRT1/Foxo-3a/p53, etc.). Whereas, downregulated ubiquitin proteasomal and apoptotic factors in CML pateints, can trigger degradation of HIF1α through proline hydroxylation. However, HIF1α showed a negative corelation with the notch1 pathway. Notch1 plays a tumor-suppressive role in CML and might have the potential to be used as a diagnostic marker along with other factors in CML patients. The outcome also revealed that oxidant treatment could not be effective in augmentation with conventional therapy because CML cells can enhance the levels of antioxidants for their survival. HIF1α might be a novel therapeutic target other than BCR/ABL1 translocation.
Collapse
Affiliation(s)
- Vivek Singh
- Department of Biochemistry, King George’s Medical University, Lucknow, India
| | - Ranjana Singh
- Department of Biochemistry, King George’s Medical University, Lucknow, India
- *Correspondence: Ranjana Singh, ;
| | - Rashmi Kushwaha
- Department of Pathology, King George’s Medical University, Lucknow, India
| | | | - Anil Kumar Tripathi
- Department of Clinical Hematology, King George’s Medical University, Lucknow, India
| | - Abbas Ali Mahdi
- Department of Biochemistry, King George’s Medical University, Lucknow, India
| |
Collapse
|
|
45
|
Thomas C, Wurzer L, Malle E, Ristow M, Madreiter-Sokolowski CT. Modulation of Reactive Oxygen Species Homeostasis as a Pleiotropic Effect of Commonly Used Drugs. FRONTIERS IN AGING 2022; 3:905261. [PMID: 35821802 PMCID: PMC9261327 DOI: 10.3389/fragi.2022.905261] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 05/18/2022] [Indexed: 01/17/2023]
Abstract
Age-associated diseases represent a growing burden for global health systems in our aging society. Consequently, we urgently need innovative strategies to counteract these pathological disturbances. Overwhelming generation of reactive oxygen species (ROS) is associated with age-related damage, leading to cellular dysfunction and, ultimately, diseases. However, low-dose ROS act as crucial signaling molecules and inducers of a vaccination-like response to boost antioxidant defense mechanisms, known as mitohormesis. Consequently, modulation of ROS homeostasis by nutrition, exercise, or pharmacological interventions is critical in aging. Numerous nutrients and approved drugs exhibit pleiotropic effects on ROS homeostasis. In the current review, we provide an overview of drugs affecting ROS generation and ROS detoxification and evaluate the potential of these effects to counteract the development and progression of age-related diseases. In case of inflammation-related dysfunctions, cardiovascular- and neurodegenerative diseases, it might be essential to strengthen antioxidant defense mechanisms in advance by low ROS level rises to boost the individual ROS defense mechanisms. In contrast, induction of overwhelming ROS production might be helpful to fight pathogens and kill cancer cells. While we outline the potential of ROS manipulation to counteract age-related dysfunction and diseases, we also raise the question about the proper intervention time and dosage.
Collapse
Affiliation(s)
- Carolin Thomas
- Laboratory of Energy Metabolism Institute of Translational Medicine Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Lia Wurzer
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Ernst Malle
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Michael Ristow
- Laboratory of Energy Metabolism Institute of Translational Medicine Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | | |
Collapse
|
|
46
|
Sirtuins and Hypoxia in EMT Control. Pharmaceuticals (Basel) 2022; 15:ph15060737. [PMID: 35745656 PMCID: PMC9228842 DOI: 10.3390/ph15060737] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 05/25/2022] [Accepted: 06/08/2022] [Indexed: 02/06/2023] Open
Abstract
Epithelial–mesenchymal transition (EMT), a physiological process during embryogenesis, can become pathological in the presence of different driving forces. Reduced oxygen tension or hypoxia is one of these forces, triggering a large number of molecular pathways with aberrant EMT induction, resulting in cancer and fibrosis onset. Both hypoxia-induced factors, HIF-1α and HIF-2α, act as master transcription factors implicated in EMT. On the other hand, hypoxia-dependent HIF-independent EMT has also been described. Recently, a new class of seven proteins with deacylase activity, called sirtuins, have been implicated in the control of both hypoxia responses, HIF-1α and HIF-2α activation, as well as EMT induction. Intriguingly, different sirtuins have different effects on hypoxia and EMT, acting as either activators or inhibitors, depending on the tissue and cell type. Interestingly, sirtuins and HIF can be activated or inhibited with natural or synthetic molecules. Moreover, recent studies have shown that these natural or synthetic molecules can be better conveyed using nanoparticles, representing a valid strategy for EMT modulation. The following review, by detailing the aspects listed above, summarizes the interplay between hypoxia, sirtuins, and EMT, as well as the possible strategies to modulate them by using a nanoparticle-based approach.
Collapse
|
|
47
|
Drapela S, Ilter D, Gomes AP. Metabolic reprogramming: a bridge between aging and tumorigenesis. Mol Oncol 2022; 16:3295-3318. [PMID: 35666002 PMCID: PMC9490145 DOI: 10.1002/1878-0261.13261] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/07/2022] [Accepted: 05/23/2022] [Indexed: 12/01/2022] Open
Abstract
Aging is the most robust risk factor for cancer development, with more than 60% of cancers occurring in those aged 60 and above. However, how aging and tumorigenesis are intertwined is poorly understood and a matter of significant debate. Metabolic changes are hallmarks of both aging and tumorigenesis. The deleterious consequences of aging include dysfunctional cellular processes, the build‐up of metabolic byproducts and waste molecules in circulation and within tissues, and stiffer connective tissues that impede blood flow and oxygenation. Collectively, these age‐driven changes lead to metabolic reprogramming in different cell types of a given tissue that significantly affects their cellular functions. Here, we put forward the idea that metabolic changes that happen during aging help create a favorable environment for tumorigenesis. We review parallels in metabolic changes that happen during aging and how these changes function both as adaptive mechanisms that enable the development of malignant phenotypes in a cell‐autonomous manner and as mechanisms that suppress immune surveillance, collectively creating the perfect environment for cancers to thrive. Hence, antiaging therapeutic strategies that target the metabolic reprogramming that occurs as we age might provide new opportunities to prevent cancer initiation and/or improve responses to standard‐of‐care anticancer therapies.
Collapse
Affiliation(s)
- Stanislav Drapela
- Department of Molecular Oncology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, USA
| | - Didem Ilter
- Department of Molecular Oncology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, USA
| | - Ana P Gomes
- Department of Molecular Oncology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, USA
| |
Collapse
|
|
48
|
Cao P, Chen Q, Shi CX, Wang LW, Gong ZJ. Sirtuin1 attenuates acute liver failure by reducing reactive oxygen species via hypoxia inducible factor 1α. World J Gastroenterol 2022; 28:1798-1813. [PMID: 35633910 PMCID: PMC9099200 DOI: 10.3748/wjg.v28.i17.1798] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 12/21/2021] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The occurrence and development of acute liver failure (ALF) is closely related to a series of inflammatory reactions, such as the production of reactive oxygen species (ROS). Hypoxia inducible factor 1α (HIF-1α) is a key factor that regulates oxygen homeostasis and redox, and the stability of HIF-1α is related to the ROS level regulated by Sirtuin (Sirt) family. The activation of Sirt1 will lead to a powerful antioxidant defense system and therapeutic effects in liver disease. However, little is known about the relationship between HIF-1α and Sirt1 in the process of ALF and the molecular mechanism.
AIM To investigate whether HIF-1α may be a target of Sirt1 deacetylation and what the effects on ALF are.
METHODS Mice were administrated lipopolysaccharide (LPS)/D-gal and exposed to hypoxic conditions as animal model, and resveratrol was used as an activator of Sirt1. The cellular model was established with L02 cells stimulated by LPS. N-acetyl-L-cysteine was used to remove ROS, and the expression of Sirt1 was inhibited by nicotinamide. Western blotting was used to detect Sirt1 and HIF-1α activity and related protein expression. The possible signaling pathways involved were analyzed by immunofluorescent staining, co-immunoprecipitation, dihydroethidium staining, and Western blotting.
RESULTS Compared with mice stimulated with LPS alone, the expression of Sirt1 decreased, the level of HIF-1α acetylation increased in hypoxic mice, and the levels of carbonic anhydrase 9 and Bcl-2-adenovirus E1B interacting protein 3 increased significantly, which was regulated by HIF-1α, indicating an increase of HIF-1α activity. Under hypoxia, the down-regulation of Sirt1 activated and acetylated HIF-1α in L02 cells. The inhibition of Sirt1 significantly aggravated this effect and the massive production of ROS. The regulation of ROS was partly through peroxisome proliferator-activated receptor alpha or AMP-activated protein kinase. Resveratrol, a Sirt1 activator, effectively relieved ALF aggravated by hypoxia, the production of ROS, and cell apoptosis. It also induced the deacetylation of HIF-1α and inhibited the activity of HIF-1α.
CONCLUSION Sirt1 may have a protective effect on ALF by inducing HIF-1α deacetylation to reduce ROS.
Collapse
Affiliation(s)
- Pan Cao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Qian Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Chun-Xia Shi
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Lu-Wen Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Zuo-Jiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| |
Collapse
|
|
49
|
Zheng K, Chen S, Hu X. Peroxisome Proliferator Activated Receptor Gamma Coactivator-1 Alpha: A Double-Edged Sword in Prostate Cancer. Curr Cancer Drug Targets 2022; 22:541-559. [PMID: 35362394 DOI: 10.2174/1568009622666220330194149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/09/2022] [Accepted: 02/17/2022] [Indexed: 12/24/2022]
Abstract
Peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1α/PPARGC1A) is a pivotal transcriptional coactivator involved in the regulation of mitochondrial metabolism, including biogenesis and oxidative metabolism. PGC-1α is finely regulated by AMP-activated protein kinases (AMPKs), the role of which in tumors remains controversial to date. In recent years, a growing amount of research on PGC-1α and tumor metabolism has emphasized its importance in a variety of tumors, including prostate cancer (PCA). Compelling evidence has shown that PGC-1α may play dual roles in promoting and inhibiting tumor development under certain conditions. Therefore, a better understanding of the critical role of PGC-1α in PCA pathogenesis will provide new insights into targeting PGC-1α for the treatment of this disease. In this review, we highlight the procancer and anticancer effects of PGC-1α in PCA and aim to provide a theoretical basis for targeting AMPK/PGC-1α to inhibit the development of PCA. In addition, our recent findings provide a candidate drug target and theoretical basis for targeting PGC-1α to regulate lipid metabolism in PCA.
Collapse
Affiliation(s)
- Kun Zheng
- Department of urology, Shanghai Sixth People\'s Hospital, 600 Yishan Road, Xuhui District, Shanghai, China
| | - Suzhen Chen
- Department of Endocrinology and Metabolism, Shanghai Sixth People\'s Hospital, Shanghai Jiao Tong University Affiliated Sixth People\'s Hospital, China
| | - Xiaoyong Hu
- Department of Urology, Shanghai Sixth People\'s Hospital, 600 Yishan Road, Xuhui District, Shanghai, China
| |
Collapse
|
|
50
|
Chavda V, Chaurasia B, Garg K, Deora H, Umana GE, Palmisciano P, Scalia G, Lu B. Molecular mechanisms of oxidative stress in stroke and cancer. BRAIN DISORDERS 2022. [DOI: 10.1016/j.dscb.2021.100029] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
|