|
1
|
Cherfi I, Nasma M, Hasan GG, Benaissa A, Benaissa Y, Laouini SE, Bouafia A, Alharthi F, Emran TB, Mallick J. Therapeutic Potential of Artemisia campestris Essential Oil: Antioxidant, Anti-Inflammatory, and Anticancer Insights From In Silico Analysis. Biomed Chromatogr 2025; 39:e70012. [PMID: 39918166 DOI: 10.1002/bmc.70012] [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: 11/29/2024] [Revised: 01/09/2025] [Accepted: 01/21/2025] [Indexed: 03/04/2025]
Abstract
Artemisia campestris subsp. campestris (tuguft) is a medicinal plant traditionally used in Algerian medicine. This study investigates the chemical composition and bioactivity of its essential oil (ACEO). Gas chromatography-mass spectrometry (GC-MS) analysis identified key compounds, including linalyl acetate (2.92%), geranyl acetate (2.45%), and eucalyptol (1.38%). ACEO demonstrated significant antioxidant activity, with IC50 values of 11.09 μg/mL (DPPH), 15.81 μg/mL (FRAP), and 22.70 μg/mL (β-carotene). It also enhanced peroxidase activity by 82.67 U/g. The anti-inflammatory effects were confirmed with an IC50 of 18.87 μg/mL. Notably, in silico molecular docking revealed that 3-cyclopentyl-N-(2-(3,4-dimethoxyphenyl)ethyl) exhibits strong binding affinity to phosphoinositide 3-kinase gamma, a target for pancreatic cancer therapy, suggesting potential anticancer activity. These findings underscore the therapeutic potential of ACEO, highlighting its antioxidant, anti-inflammatory, and anticancer properties.
Collapse
Affiliation(s)
- Inasse Cherfi
- Faculty of Natural Science and Life, Department of Molecular and Cellular Biology, El Oued University, El Oued, Algeria
- Laboratory Biology, Environment, and Health, Faculty of Natural Sciences and Life, El-Oued University, El-Oued, Algeria
| | - Mahboub Nasma
- Faculty of Natural Science and Life, Department of Molecular and Cellular Biology, El Oued University, El Oued, Algeria
- Laboratory Biology, Environment, and Health, Faculty of Natural Sciences and Life, El-Oued University, El-Oued, Algeria
| | - Gamil Gamal Hasan
- VPRS Laboratory, Chemistry Department, Faculty of Mathematics and Matter Sciences, University of KASDI Merbah, Ouargla, Algeria
- Laboratory of Biotechnology Biomaterial and Condensed Matter, Faculty of Technology of Technology, University of El Oued, El Oued, Algeria
| | - Abir Benaissa
- Laboratory of Biotechnology Biomaterial and Condensed Matter, Faculty of Technology of Technology, University of El Oued, El Oued, Algeria
| | - Youcef Benaissa
- VPRS Laboratory, Chemistry Department, Faculty of Mathematics and Matter Sciences, University of KASDI Merbah, Ouargla, Algeria
| | - Salah Eddine Laouini
- Laboratory of Biotechnology Biomaterial and Condensed Matter, Faculty of Technology of Technology, University of El Oued, El Oued, Algeria
- Department of Process Engineering, Faculty of Technology, University of El Oued, El-Oued, Algeria
| | - Abderrhmane Bouafia
- Laboratory of Biotechnology Biomaterial and Condensed Matter, Faculty of Technology of Technology, University of El Oued, El Oued, Algeria
- Department of Process Engineering, Faculty of Technology, University of El Oued, El-Oued, Algeria
| | - Fahad Alharthi
- Department of Chemistry, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Talha Bin Emran
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
- Legorreta Cancer Center, Brown University, Providence, Rhode Island, USA
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Jewel Mallick
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh
| |
Collapse
|
|
2
|
Agrawal S, Podber A, Gillespie M, Dietz N, Hansen LA, Nandipati KC. Regulation of pro-apoptotic and anti-apoptotic factors in obesity-related esophageal adenocarcinoma. Mol Biol Rep 2024; 51:1049. [PMID: 39395071 PMCID: PMC11470870 DOI: 10.1007/s11033-024-09931-6] [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: 03/31/2024] [Accepted: 09/10/2024] [Indexed: 10/14/2024]
Abstract
BACKGROUND Obesity is a risk factor for esophageal adenocarcinoma (EAC). It was reported that obesity -associated inflammation correlates with insulin resistance and increased risk of EAC. The objective of the study is to investigate the role of obesity associated inflammatory mediators in the development of EAC. METHODS We included 23 obese and nonobese patients with EAC or with or without Barrett's esophagus (BE) after IRB approval. We collected 23 normal, 10 BE, and 19 EAC tissue samples from endoscopy or esophagectomy. The samples were analyzed for the expression levels of pro-apoptotic and anti-apoptotic factors, PKC-δ, cIAP2, FLIP, IGF-1, Akt, NF-kB and Ki67 by immunofluorescence and RT-PCR. We compared the expression levels between normal, BE, and EAC tissue using Students' t-test between two groups. RESULTS Our results showed decreased gene and protein expression of pro-apoptotic factors (bad, bak and bax) and increased expression of anti-apoptotic factors (bcl-2, Bcl-xL) in BE and EAC compared to normal tissues. There was increased gene and protein expression of PKC-δ, cIAP2, FLIP, NF-kB, IGF-1, Akt, and Ki67 in BE and EAC samples compared to normal esophagus. Further, an increased folds changes in mRNA expression of proapoptotic factors, antiapoptotic factors, PKC-δ, IGF-1, Akt, and Ki-67 was associated with obesity. CONCLUSION Patients with EAC had increased expression of cIAP2 and FLIP, and PKC-δ which is associated with inhibition of apoptosis and possible progression of esophageal adenocarcinoma.
Collapse
Affiliation(s)
- Swati Agrawal
- School of Medicine, Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA
- Department of Surgery, School of Medicine, Creighton University, 7710 Mercy Road, Education Building, Suite 501, Omaha, NE, 68124, USA
| | - Anna Podber
- School of Medicine, Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA
- Department of Surgery, School of Medicine, Creighton University, 7710 Mercy Road, Education Building, Suite 501, Omaha, NE, 68124, USA
| | - Megan Gillespie
- School of Medicine, Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA
- Department of Surgery, School of Medicine, Creighton University, 7710 Mercy Road, Education Building, Suite 501, Omaha, NE, 68124, USA
| | - Nick Dietz
- Department of Pathology, School of Medicine, Creighton University, 7710 Mercy Road, Education Building, Suite 501, Omaha, NE, 68124, USA
| | - Laura A Hansen
- School of Medicine, Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA
- Department of Biomedical Sciences, Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA
| | - Kalyana C Nandipati
- School of Medicine, Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA.
- Department of Surgery, School of Medicine, Creighton University, 7710 Mercy Road, Education Building, Suite 501, Omaha, NE, 68124, USA.
| |
Collapse
|
|
3
|
Hassan MS, Johnson C, Ponna S, Scofield D, Awasthi N, von Holzen U. Inhibition of Insulin-like Growth Factor 1 Receptor/Insulin Receptor Signaling by Small-Molecule Inhibitor BMS-754807 Leads to Improved Survival in Experimental Esophageal Adenocarcinoma. Cancers (Basel) 2024; 16:3175. [PMID: 39335147 PMCID: PMC11430189 DOI: 10.3390/cancers16183175] [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: 08/12/2024] [Revised: 09/04/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
The insulin-like growth factor-1 (IGF-1) and insulin axes are upregulated in obesity and obesity-associated esophageal adenocarcinoma (EAC). Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a contemporary nanotechnology-based paclitaxel (PT) bound to human albumin, ensuring its solubility in water rather than a toxic solvent. Here, we examined the benefits of inhibiting insulin-like growth factor-1 receptor/insulin receptor (IGF-1/IR) signaling and the enhancement of nab-paclitaxel effects by inclusion of the small-molecule inhibitor BMS-754807 using both in vitro and in vivo models of EAC. Using multiple EAC cell lines, BMS-754807 and nab-paclitaxel were evaluated as mono and combination therapies for in vitro effects on cell proliferation, cell death, and cell movement. We then analyzed the in vivo anticancer potency with survival improvement with BMS-754807 and nab-paclitaxel mono and combination therapies. BMS-754807 monotherapy suppressed in vitro cell proliferation and wound healing while increasing apoptosis. BMS-754807, when combined with nab-paclitaxel, enhanced those effects on the inhibition of cell proliferation, increment in cell apoptosis, and inhibition of wound healing. BMS-754807 with nab-paclitaxel produced substantially greater antitumor effects by increasing in vivo apoptosis, leading to increased mice survival compared to those of BMS-754807 or nab-paclitaxel monotherapy. Our outcomes support the use of BMS-754807, alone and in combination with nab-paclitaxel, as an efficient and innovative treatment choice for EAC.
Collapse
Affiliation(s)
- Md Sazzad Hassan
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA; (N.A.)
- Harper Cancer Research Institute, South Bend, IN 46617, USA
| | - Chloe Johnson
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Saisantosh Ponna
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Dimitri Scofield
- Department of Biology, Indiana University, South Bend, IN 47405, USA
| | - Niranjan Awasthi
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA; (N.A.)
- Harper Cancer Research Institute, South Bend, IN 46617, USA
| | - Urs von Holzen
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA; (N.A.)
- Harper Cancer Research Institute, South Bend, IN 46617, USA
- Goshen Center for Cancer Care, Goshen, IN 46526, USA
- School of Medicine, University of Basel, 4056 Basel, Switzerland
| |
Collapse
|
|
4
|
Verma J, Vashisth H. Structural Models for a Series of Allosteric Inhibitors of IGF1R Kinase. Int J Mol Sci 2024; 25:5368. [PMID: 38791406 PMCID: PMC11121299 DOI: 10.3390/ijms25105368] [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: 04/07/2024] [Revised: 05/09/2024] [Accepted: 05/11/2024] [Indexed: 05/26/2024] Open
Abstract
The allosteric inhibition of insulin-like growth factor receptor 1 kinase (IGF1RK) is a potential strategy to overcome selectivity barriers for targeting receptor tyrosine kinases. We constructed structural models of a series of 12 indole-butyl-amine derivatives that have been reported as allosteric inhibitors of IGF1RK. We further studied the dynamics and interactions of each inhibitor in the allosteric pocket via all-atom explicit-solvent molecular dynamics (MD) simulations. We discovered that a bulky carbonyl substitution at the R1 indole ring is structurally unfavorable for inhibitor binding in the IGF1RK allosteric pocket. Moreover, we found that the most potent derivative (termed C11) acquires a distinct conformation: forming an allosteric pocket channel with better shape complementarity and interactions with the receptor. In addition to a hydrogen-bonding interaction with V1063, the cyano derivative C11 forms a stable hydrogen bond with M1156, which is responsible for its unique binding conformation in the allosteric pocket. Our findings show that the positioning of chemical substituents with different pharmacophore features at the R1 indole ring influences molecular interactions and binding conformations of indole-butyl-amine derivatives and, hence, dramatically affects their potencies. Our results provide a structural framework for the design of allosteric inhibitors with improved affinities and specificities against IGF1RK.
Collapse
Affiliation(s)
- Jyoti Verma
- Department of Chemical Engineering and Bioengineering, University of New Hampshire, Durham, NH 03824, USA;
| | - Harish Vashisth
- Department of Chemical Engineering and Bioengineering, University of New Hampshire, Durham, NH 03824, USA;
- Department of Chemistry, University of New Hampshire, Durham, NH 03824, USA
- Integrated Applied Mathematics Program, University of New Hampshire, Durham, NH 03824, USA
- Molecular and Cellular Biotechnology Program, University of New Hampshire, Durham, NH 03824, USA
| |
Collapse
|
|
5
|
Verma J, Vashisth H. Structural Models for a Series of Allosteric Inhibitors of IGF1R Kinase. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.04.588115. [PMID: 38617226 PMCID: PMC11014618 DOI: 10.1101/2024.04.04.588115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
The allosteric inhibition of Insulin-like Growth Factor Receptor 1 Kinase (IGF1RK) is a potential strategy to overcome selectivity barriers in targeting receptor tyrosine kinases. We constructed structural models of a series of 12 indole-butyl-amine derivatives which have been reported as allosteric inhibitors of IGF1RK. We further studied dynamics and interactions of each inhibitor in the allosteric pocket via all-atom explicit-solvent molecular dynamics (MD) simulations. We discovered that a bulky carbonyl substitution at the R1 indole ring is structurally unfavorable for inhibitor binding in the IGF1RK allosteric pocket. Moreover, we found that the most potent derivative (termed C11) acquires a distinct conformation, forming an allosteric pocket channel with better shape complementarity and interactions with the receptor. In addition to a hydrogen bonding interaction with V1063, the cyano derivative C11 forms a stable hydrogen bond with M1156, which is responsible for its unique binding conformation in the allosteric pocket. Our findings show that the position of chemical substituents at the R1 indole ring with different pharmacophore features influences molecular interactions and binding conformations of the indole-butyl-amine derivatives, hence dramatically affecting their potencies. Our results provide a structural framework for the design of allosteric inhibitors with improved affinities and specificities against IGF1RK.
Collapse
Affiliation(s)
- Jyoti Verma
- Department of Chemical Engineering and Bioengineering, University of New Hampshire, Durham, NH 03824, USA
| | - Harish Vashisth
- Department of Chemical Engineering and Bioengineering, University of New Hampshire, Durham, NH 03824, USA
- Department of Chemistry, University of New Hampshire, Durham, NH 03824, USA
- Integrated Applied Mathematics Program, University of New Hampshire, Durham, NH 03824, USA
- Molecular and Cellular Biotechnology Program, University of New Hampshire, Durham, NH 03824, USA
| |
Collapse
|
|
6
|
Xu D, Li Y, Yin S, Huang F. Strategies to address key challenges of metallacycle/metallacage-based supramolecular coordination complexes in biomedical applications. Chem Soc Rev 2024; 53:3167-3204. [PMID: 38385584 DOI: 10.1039/d3cs00926b] [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: 02/23/2024]
Abstract
Owing to their capacity for dynamically linking two or more functional molecules, supramolecular coordination complexes (SCCs), exemplified by two-dimensional (2D) metallacycles and three-dimensional (3D) metallacages, have gained increasing significance in biomedical applications. However, their inherent hydrophobicity and self-assembly driven by heavy metal ions present common challenges in their applications. These challenges can be overcome by enhancing the aqueous solubility and in vivo circulation stability of SCCs, alongside minimizing their side effects during treatment. Addressing these challenges is crucial for advancing the fundamental research of SCCs and their subsequent clinical translation. In this review, drawing on extensive contemporary research, we offer a thorough and systematic analysis of the strategies employed by SCCs to surmount these prevalent yet pivotal obstacles. Additionally, we explore further potential challenges and prospects for the broader application of SCCs in the biomedical field.
Collapse
Affiliation(s)
- Dongdong Xu
- Key Laboratory of Organosilicon Chemistry and Materials Technology of Ministry of Education, College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 311121, P. R. China.
| | - Yang Li
- Key Laboratory of Organosilicon Chemistry and Materials Technology of Ministry of Education, College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 311121, P. R. China.
| | - Shouchun Yin
- Key Laboratory of Organosilicon Chemistry and Materials Technology of Ministry of Education, College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 311121, P. R. China.
| | - Feihe Huang
- Stoddart Institute of Molecular Science, Department of Chemistry, Zhejiang University, Hangzhou 310058, P. R. China.
- Zhejiang-Israel Joint Laboratory of Self-Assembling Functional Materials, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, 311215, P. R. China
| |
Collapse
|
|
7
|
Shahid A, Santos SG, Lin C, Huang Y. Role of Insulin-like Growth Factor-1 Receptor in Tobacco Smoking-Associated Lung Cancer Development. Biomedicines 2024; 12:563. [PMID: 38540176 PMCID: PMC10967781 DOI: 10.3390/biomedicines12030563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 02/23/2024] [Accepted: 02/29/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer remains a significant global health concern, with lung cancer consistently leading as one of the most common malignancies. Genetic aberrations involving receptor tyrosine kinases (RTKs) are known to be associated with cancer initiation and development, but RTK involvement in smoking-associated lung cancer cases is not well understood. The Insulin-like Growth Factor 1 Receptor (IGF-1R) is a receptor that plays a critical role in lung cancer development. Its signaling pathway affects the growth and survival of cancer cells, and high expression is linked to poor prognosis and resistance to treatment. Several reports have shown that by activating IGF-1R, tobacco smoke-related carcinogens promote lung cancer and chemotherapy resistance. However, the relationship between IGF-1R and cancer is complex and can vary depending on the type of cancer. Ongoing investigations are focused on developing therapeutic strategies to target IGF-1R and overcome chemotherapy resistance. Overall, this review explores the intricate connections between tobacco smoke-specific carcinogens and the IGF-1R pathway in lung carcinogenesis. This review further highlights the challenges in using IGF-1R inhibitors as targeted therapy for lung cancer due to structural similarities with insulin receptors. Overcoming these obstacles may require a comprehensive approach combining IGF-1R inhibition with other selective agents for successful cancer treatment.
Collapse
Affiliation(s)
- Ayaz Shahid
- Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA;
| | - Shaira Gail Santos
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Carol Lin
- Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA;
| | - Ying Huang
- Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA;
| |
Collapse
|
|
8
|
Lee IY, Hanft S, Schulder M, Judy KD, Wong ET, Elder JB, Evans LT, Zuccarello M, Wu J, Aulakh S, Agarwal V, Ramakrishna R, Gill BJ, Quiñones-Hinojosa A, Brennan C, Zacharia BE, Silva Correia CE, Diwanji M, Pennock GK, Scott C, Perez-Olle R, Andrews DW, Boockvar JA. Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients. Future Oncol 2024; 20:579-591. [PMID: 38060340 DOI: 10.2217/fon-2023-0702] [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] [Indexed: 03/20/2024] Open
Abstract
Standard-of-care first-line therapy for patients with newly diagnosed glioblastoma (ndGBM) is maximal safe surgical resection, then concurrent radiotherapy and temozolomide, followed by maintenance temozolomide. IGV-001, the first product of the Goldspire™ platform, is a first-in-class autologous immunotherapeutic product that combines personalized whole tumor-derived cells with an antisense oligonucleotide (IMV-001) in implantable biodiffusion chambers, with the intent to induce a tumor-specific immune response in patients with ndGBM. Here, we describe the design and rationale of a randomized, double-blind, phase IIb trial evaluating IGV-001 compared with placebo, both followed by standard-of-care treatment in patients with ndGBM. The primary end point is progression-free survival, and key secondary end points include overall survival and safety.
Collapse
Affiliation(s)
- Ian Y Lee
- Henry Ford Health System, Detroit, MI 48202, USA
| | - Simon Hanft
- Westchester Medical Center, Valhalla, NY 10595, USA
| | - Michael Schulder
- Northwell Health at North Shore University Hospital, Lake Success, NY 11030, USA
| | - Kevin D Judy
- Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Eric T Wong
- Rhode Island Hospital & The Warren Alpert Medical School of Brown University, Providence, RI 02912, USA
| | | | - Linton T Evans
- Dartmouth Hitchcock Medical Center, Lebanon, NH 03766, USA
| | - Mario Zuccarello
- University of Cincinnati Medical Center, Cincinnati, OH 45219, USA
| | - Julian Wu
- Tufts Medical Center, Boston, MA 02111, USA
| | | | | | | | - Brian J Gill
- Columbia University Medical Center, New York, NY 10019, USA
| | | | - Cameron Brennan
- Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
9
|
Moghbeli M, Taghehchian N, Akhlaghipour I, Samsami Y, Maharati A. Role of forkhead box proteins in regulation of doxorubicin and paclitaxel responses in tumor cells: A comprehensive review. Int J Biol Macromol 2023; 248:125995. [PMID: 37499722 DOI: 10.1016/j.ijbiomac.2023.125995] [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: 06/20/2023] [Revised: 07/18/2023] [Accepted: 07/24/2023] [Indexed: 07/29/2023]
Abstract
Chemotherapy is one of the common first-line therapeutic methods in cancer patients. Despite the significant effects in improving the quality of life and survival of patients, chemo resistance is observed in a significant part of cancer patients, which leads to tumor recurrence and metastasis. Doxorubicin (DOX) and paclitaxel (PTX) are used as the first-line drugs in a wide range of tumors; however, DOX/PTX resistance limits their use in cancer patients. Considering the DOX/PTX side effects in normal tissues, identification of DOX/PTX resistant cancer patients is required to choose the most efficient therapeutic strategy for these patients. Investigating the molecular mechanisms involved in DOX/PTX response can help to improve the prognosis in cancer patients. Several cellular processes such as drug efflux, autophagy, and DNA repair are associated with chemo resistance that can be regulated by transcription factors as the main effectors in signaling pathways. Forkhead box (FOX) family of transcription factor has a key role in regulating cellular processes such as cell differentiation, migration, apoptosis, and proliferation. FOX deregulations have been associated with resistance to chemotherapy in different cancers. Therefore, we discussed the role of FOX protein family in DOX/PTX response. It has been reported that FOX proteins are mainly involved in DOX/PTX response by regulation of drug efflux, autophagy, structural proteins, and signaling pathways such as PI3K/AKT, NF-kb, and JNK. This review is an effective step in introducing the FOX protein family as the reliable prognostic markers and therapeutic targets in cancer patients.
Collapse
Affiliation(s)
- Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Negin Taghehchian
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yalda Samsami
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
10
|
Wolde HF, Molla MD, Aragie H, Adugna DG, Teferi ET, Melese EB, Assefa YA, Kifle H, Worku YB, Belay DG, Kibret AA. High burden of diabetes and prediabetes among cancer patients at University of Gondar comprehensive specialized hospital, Northwest Ethiopia. Sci Rep 2023; 13:9431. [PMID: 37296304 PMCID: PMC10256839 DOI: 10.1038/s41598-023-36472-y] [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: 11/10/2022] [Accepted: 06/04/2023] [Indexed: 06/12/2023] Open
Abstract
Cancer and diabetes mellitus (DM) are diagnosed within the same individual more frequently and share common risk factors. Although diabetes among cancer patients may result in more aggressive clinical courses of cancer, there is limited evidence about its burden and associated factors. Hence, this study aimed to assess the burden of diabetes and prediabetes among cancer patients and its associated factors. Institution-based cross-sectional study was conducted at the University of Gondar comprehensive specialized hospital from 10 January to 10 March 2021. A systematic random sampling technique was used to select 423 cancer patients. The data was collected using a structured interviewer-administered questionnaire. Prediabetes and diabetes diagnosis was made based on World Health Organization (WHO) criteria. Bi-variable and multivariable binary logistic regression models were fitted to identify factors associated with the outcome. Adjusted Odds Ratio (AOR) with a 95% confidence interval was estimated to show the direction and strength of associations. Variables with a p-value less than 0.05 in the multivariable model were considered significantly associated with the outcome. The final analysis was based on 384 patients with cancer. The proportion of prediabetes and diabetes was 56.8% (95% CI 51.7, 61.7) and 16.7% (95% CI 13.3, 20.8), respectively. Alcohol consumption was found to increase the odds of elevated blood sugar among cancer patients (AOR: 1.96; 95%CI: 1.11, 3.46). The burden of prediabetes and diabetes is alarmingly high among cancer patients. Besides, alcohol consumption was found to increase the odds of having elevated blood sugar among cancer patients. Hence, it is essential to recognize cancer patients are at high risk of having elevated blood sugar and design strategies to integrate diabetes and cancer care.
Collapse
Affiliation(s)
- Haileab Fekadu Wolde
- Department of Epidemiology and Biostatistics, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Meseret Derbew Molla
- Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Hailu Aragie
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Dagnew Getnet Adugna
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Ephrem Tafesse Teferi
- Department of Internal Medicine School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Endalkachew Belayneh Melese
- Department of Internal Medicine School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Yohannes Awoke Assefa
- Department of Occupational Therapy School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Habtu Kifle
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Yilkal Belete Worku
- Department of Internal Medicine School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Daniel Gashaneh Belay
- Department of Epidemiology and Biostatistics, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Anteneh Ayelign Kibret
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia.
| |
Collapse
|
|
11
|
Hassan N, Efing J, Kiesel L, Bendas G, Götte M. The Tissue Factor Pathway in Cancer: Overview and Role of Heparan Sulfate Proteoglycans. Cancers (Basel) 2023; 15:1524. [PMID: 36900315 PMCID: PMC10001432 DOI: 10.3390/cancers15051524] [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: 01/30/2023] [Revised: 02/24/2023] [Accepted: 02/26/2023] [Indexed: 03/05/2023] Open
Abstract
Historically, the only focus on tissue factor (TF) in clinical pathophysiology has been on its function as the initiation of the extrinsic coagulation cascade. This obsolete vessel-wall TF dogma is now being challenged by the findings that TF circulates throughout the body as a soluble form, a cell-associated protein, and a binding microparticle. Furthermore, it has been observed that TF is expressed by various cell types, including T-lymphocytes and platelets, and that certain pathological situations, such as chronic and acute inflammatory states, and cancer, may increase its expression and activity. Transmembrane G protein-coupled protease-activated receptors can be proteolytically cleaved by the TF:FVIIa complex that develops when TF binds to Factor VII (PARs). The TF:FVIIa complex can activate integrins, receptor tyrosine kinases (RTKs), and PARs in addition to PARs. Cancer cells use these signaling pathways to promote cell division, angiogenesis, metastasis, and the maintenance of cancer stem-like cells. Proteoglycans play a crucial role in the biochemical and mechanical properties of the cellular extracellular matrix, where they control cellular behavior via interacting with transmembrane receptors. For TFPI.fXa complexes, heparan sulfate proteoglycans (HSPGs) may serve as the primary receptor for uptake and degradation. The regulation of TF expression, TF signaling mechanisms, their pathogenic effects, and their therapeutic targeting in cancer are all covered in detail here.
Collapse
Affiliation(s)
- Nourhan Hassan
- Department of Gynecology and Obstetrics, Münster University Hospital, Domagkstrasse 11, 48149 Münster, Germany
- Biotechnology/Biomolecular Chemistry Program, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Janes Efing
- Department of Gynecology and Obstetrics, Münster University Hospital, Domagkstrasse 11, 48149 Münster, Germany
| | - Ludwig Kiesel
- Department of Gynecology and Obstetrics, Münster University Hospital, Domagkstrasse 11, 48149 Münster, Germany
| | - Gerd Bendas
- Pharmaceutical Department, University Bonn, An der Immenburg 4, 53225 Bonn, Germany
| | - Martin Götte
- Department of Gynecology and Obstetrics, Münster University Hospital, Domagkstrasse 11, 48149 Münster, Germany
| |
Collapse
|
|
12
|
Nagaraj K, Sarfstein R, Laron Z, Werner H. Long-Term IGF1 Stimulation Leads to Cellular Senescence via Functional Interaction with the Thioredoxin-Interacting Protein, TXNIP. Cells 2022; 11:cells11203260. [PMID: 36291127 PMCID: PMC9601129 DOI: 10.3390/cells11203260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 10/08/2022] [Accepted: 10/11/2022] [Indexed: 12/05/2022] Open
Abstract
The growth hormone (GH)–insulin-like growth factor-1 (IGF1) signaling pathway plays a major role in orchestrating cellular interactions, metabolism, growth and aging. Studies from worms to mice showed that downregulated activity of the GH/IGF1 pathway could be beneficial for the extension of lifespan. Laron syndrome (LS) is an inherited autosomal recessive disorder caused by molecular defects of the GH receptor (GHR) gene, leading to congenital IGF1 deficiency. Life-long exposure to minute endogenous IGF1 levels in LS is associated with low stature as well as other endocrine and metabolic deficits. Epidemiological surveys reported that patients with LS have a reduced risk of developing cancer. Studies conducted on LS-derived lymphoblastoid cells led to the identification of a novel link between IGF1 and thioredoxin-interacting protein (TXNIP), a multifunctional mitochondrial protein. TXNIP is highly expressed in LS patients and plays a critical role in cellular redox regulation by thioredoxin. Given that IGF1 affects the levels of TXNIP under various stress conditions, including high glucose and oxidative stress, we hypothesized that the IGF1–TXNIP axis plays an essential role in helping maintain a physiological balance in cellular homeostasis. In this study, we show that TXNIP is vital for the cell fate choice when cells are challenged by various stress signals. Furthermore, prolonged IGF1 treatment leads to the establishment of a premature senescence phenotype characterized by a unique senescence network signature. Combined IGF1/TXNIP-induced premature senescence can be associated with a typical secretory inflammatory phenotype that is mediated by STAT3/IL-1A signaling. Finally, these mechanistic insights might help with the understanding of basic aspects of IGF1-related pathologies in the clinical setting.
Collapse
Affiliation(s)
- Karthik Nagaraj
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Rive Sarfstein
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Zvi Laron
- Endocrinology and Diabetes Research Unit, Schneider Children’s Medical Center, Petah Tikva 49292, Israel
| | - Haim Werner
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
- Correspondence: ; Tel.: +972-3-6408542; Fax: +972-3-6405055
| |
Collapse
|
|
13
|
Erlandsson MC, Erdogan S, Wasén C, Andersson KME, Silfverswärd ST, Pullerits R, Bemark M, Bokarewa MI. IGF1R signalling is a guardian of self-tolerance restricting autoantibody production. Front Immunol 2022; 13:958206. [PMID: 36105797 PMCID: PMC9464816 DOI: 10.3389/fimmu.2022.958206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/01/2022] [Indexed: 11/18/2022] Open
Abstract
Objective Insulin-like growth factor 1 receptor (IGF1R) acts at the crossroad between immunity and cancer, being an attractive therapeutic target in these areas. IGF1R is broadly expressed by antigen-presenting cells (APC). Using mice immunised with the methylated albumin from bovine serum (BSA-immunised mice) and human CD14+ APCs, we investigated the role that IGF1R plays during adaptive immune responses. Methods The mBSA-immunised mice were treated with synthetic inhibitor NT157 or short hairpin RNA to inhibit IGF1R signalling, and spleens were analysed by immunohistology and flow cytometry. The levels of autoantibody and cytokine production were measured by microarray or conventional ELISA. The transcriptional profile of CD14+ cells from blood of 55 patients with rheumatoid arthritis (RA) was analysed with RNA-sequencing. Results Inhibition of IGF1R resulted in perifollicular infiltration of functionally compromised S256-phosphorylated FoxO1+ APCs, and an increased frequency of IgM+CD21+ B cells, which enlarged the marginal zone (MZ). Enlargement of MHCII+CD11b+ APCs ensured favourable conditions for their communication with IgM+ B cells in the MZ. The reduced expression of ICOSL and CXCR5 by APCs after IGF1R inhibition led to impaired T cell control, which resulted in autoreactivity of extra-follicular B cells and autoantibody production. In the clinical setting, the low expression of IGF1R on CD14+ APCs was associated with an involuted FOXO pathway, non-inflammatory cell metabolism and a high IL10 production characteristic for tolerogenic macrophages. Furthermore, autoantibody positivity was associated with low IGF1R signalling in CD14+ APCs. Conclusions In experimental model and in patient material, this study demonstrates that IGF1R plays an important role in preventing autoimmunity. The study raises awareness of that immune tolerance may be broken during therapeutic IGF1R targeting.
Collapse
Affiliation(s)
- Malin C. Erlandsson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
- Rheumatology Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Seval Erdogan
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Caroline Wasén
- Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, United States
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
| | - Karin M. E. Andersson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Sofia T. Silfverswärd
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Rille Pullerits
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Immunology and Transfusion Medicine, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Mats Bemark
- Department of Clinical Immunology and Transfusion Medicine, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maria I. Bokarewa
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
- Rheumatology Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden
- *Correspondence: Maria I. Bokarewa,
| |
Collapse
|
|
14
|
Karcini A, Lazar IM. The SKBR3 cell-membrane proteome reveals telltales of aberrant cancer cell proliferation and targets for precision medicine applications. Sci Rep 2022; 12:10847. [PMID: 35760832 PMCID: PMC9237123 DOI: 10.1038/s41598-022-14418-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 06/07/2022] [Indexed: 12/14/2022] Open
Abstract
The plasma membrane proteome resides at the interface between the extra- and intra-cellular environment and through its various roles in signal transduction, immune recognition, nutrient transport, and cell-cell/cell-matrix interactions plays an absolutely critical role in determining the fate of a cell. Our work was aimed at exploring the cell-membrane proteome of a HER2+ breast-cancer cell line (SKBR3) to identify triggers responsible for uncontrolled cell proliferation and intrinsic resources that enable detection and therapeutic interventions. To mimic environmental conditions that enable cancer cells to evolve adaptation/survival traits, cell culture was performed under serum-rich and serum-deprived conditions. Proteomic analysis enabled the identification of ~ 2000 cell-membrane proteins. Classification into proteins with receptor/enzymatic activity, CD antigens, transporters, and cell adhesion/junction proteins uncovered overlapping roles in processes that drive cell growth, apoptosis, differentiation, immune response, adhesion and migration, as well as alternate pathways for proliferation. The large number of tumor markers (> 50) and putative drug targets (> 100) exposed a vast potential for yet unexplored detection and targeting opportunities, whereas the presence of 15 antigen immunological markers enabled an assessment of epithelial, mesenchymal or stemness characteristics. Serum-starved cells displayed altered processes related to mitochondrial OXPHOS/ATP synthesis, protein folding and localization, while serum-treated cells exhibited attributes that support tissue invasion and metastasis. Altogether, our findings advance the understanding of the biological triggers that sustain aberrant cancer cell proliferation, survival and development of resistance to therapeutic drugs, and reveal vast innate opportunities for guiding immunological profiling and precision medicine applications aimed at target selection or drug discovery.
Collapse
Affiliation(s)
- Arba Karcini
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Iulia M Lazar
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061, USA.
- Fralin Life Sciences Institute, Virginia Tech, Blacksburg, VA, 24061, USA.
- Virginia Tech Carilion School of Medicine, Roanoke, VA, 24016, USA.
| |
Collapse
|
|
15
|
Correlation of nuclear pIGF-1R/IGF-1R and YAP/TAZ in a tissue microarray with outcomes in osteosarcoma patients. Oncotarget 2022; 13:521-533. [PMID: 35284040 PMCID: PMC8906536 DOI: 10.18632/oncotarget.28215] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 02/24/2022] [Indexed: 11/25/2022] Open
Abstract
Osteosarcoma (OS) is a genetically diverse bone cancer that lacks a consistent targetable mutation. Recent studies suggest the IGF/PI3K/mTOR pathway and YAP/TAZ paralogs regulate cell fate and proliferation in response to biomechanical cues within the tumor microenvironment. How this occurs and their implication upon osteosarcoma survival, remains poorly understood. Here, we show that IGF-1R can translocate into the nucleus, where it may act as part of a transcription factor complex. To explore the relationship between YAP/TAZ and total and nuclear phosphorylated IGF-1R (pIGF-1R), we evaluated sequential tumor sections from a 37-patient tissue microarray by confocal microscopy. Next, we examined the relationship between stained markers, clinical disease characteristics, and patient outcomes. The nuclear to cytoplasmic ratios (N:C ratio) of YAP and TAZ strongly correlated with nuclear pIGF-1R (r = 0.522, p = 0.001 for each pair). Kaplan-Meier analyses indicated that nuclear pIGF-1R predicted poor overall survival, a finding confirmed in the Cox proportional hazards model. Though additional investigation in a larger prospective study will be required to validate the prognostic accuracy of these markers, our results may have broad implications for the new class of YAP, TAZ, AXL, or TEAD inhibitors that have reached early phase clinical trials this year.
Collapse
|
|
16
|
Silver MJ, Saffari A, Kessler NJ, Chandak GR, Fall CHD, Issarapu P, Dedaniya A, Betts M, Moore SE, Routledge MN, Herceg Z, Cuenin C, Derakhshan M, James PT, Monk D, Prentice AM. Environmentally sensitive hotspots in the methylome of the early human embryo. eLife 2022; 11:e72031. [PMID: 35188105 PMCID: PMC8912923 DOI: 10.7554/elife.72031] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 02/18/2022] [Indexed: 11/26/2022] Open
Abstract
In humans, DNA methylation marks inherited from gametes are largely erased following fertilisation, prior to construction of the embryonic methylome. Exploiting a natural experiment of seasonal variation including changes in diet and nutritional status in rural Gambia, we analysed three datasets covering two independent child cohorts and identified 259 CpGs showing consistent associations between season of conception (SoC) and DNA methylation. SoC effects were most apparent in early infancy, with evidence of attenuation by mid-childhood. SoC-associated CpGs were enriched for metastable epialleles, parent-of-origin-specific methylation and germline differentially methylated regions, supporting a periconceptional environmental influence. Many SoC-associated CpGs overlapped enhancers or sites of active transcription in H1 embryonic stem cells and fetal tissues. Half were influenced but not determined by measured genetic variants that were independent of SoC. Environmental 'hotspots' providing a record of environmental influence at periconception constitute a valuable resource for investigating epigenetic mechanisms linking early exposures to lifelong health and disease.
Collapse
Affiliation(s)
- Matt J Silver
- Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical MedicineGambiaUnited Kingdom
| | - Ayden Saffari
- Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical MedicineGambiaUnited Kingdom
| | - Noah J Kessler
- Department of Genetics, University of CambridgeCambridgeUnited Kingdom
| | - Gririraj R Chandak
- Genomic Research on Complex Diseases, CSIR-Centre for Cellular and Molecular BiologyHyderabadIndia
| | - Caroline HD Fall
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General HospitalSouthamptonUnited Kingdom
| | - Prachand Issarapu
- Genomic Research on Complex Diseases, CSIR-Centre for Cellular and Molecular BiologyHyderabadIndia
| | - Akshay Dedaniya
- Genomic Research on Complex Diseases, CSIR-Centre for Cellular and Molecular BiologyHyderabadIndia
| | - Modupeh Betts
- Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical MedicineGambiaUnited Kingdom
| | - Sophie E Moore
- Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical MedicineGambiaUnited Kingdom
- Department of Women and Children's Health, King's College LondonLondonUnited Kingdom
| | - Michael N Routledge
- School of Medicine, University of LeedsLeedsUnited Kingdom
- School of Food and Biological Engineering, Jiangsu UniversityZhenjiangChina
| | - Zdenko Herceg
- Epigenomics and Mechanisms Branch, International Agency For Research On CancerLyonFrance
| | - Cyrille Cuenin
- Epigenomics and Mechanisms Branch, International Agency For Research On CancerLyonFrance
| | - Maria Derakhshan
- Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical MedicineGambiaUnited Kingdom
| | - Philip T James
- Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical MedicineGambiaUnited Kingdom
| | - David Monk
- Biomedical Research Centre, University of East AngliaNorwichUnited Kingdom
- Bellvitge Institute for Biomedical ResearchBarcelonaSpain
| | - Andrew M Prentice
- Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical MedicineGambiaUnited Kingdom
| |
Collapse
|
|
17
|
Bin-Jumah MN, Nadeem MS, Gilani SJ, Al-Abbasi FA, Ullah I, Alzarea SI, Ghoneim MM, Alshehri S, Uddin A, Murtaza BN, Kazmi I. Genes and Longevity of Lifespan. Int J Mol Sci 2022; 23:1499. [PMID: 35163422 PMCID: PMC8836117 DOI: 10.3390/ijms23031499] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 01/04/2022] [Accepted: 01/26/2022] [Indexed: 12/12/2022] Open
Abstract
Aging is a complex process indicated by low energy levels, declined physiological activity, stress induced loss of homeostasis leading to the risk of diseases and mortality. Recent developments in medical sciences and an increased availability of nutritional requirements has significantly increased the average human lifespan worldwide. Several environmental and physiological factors contribute to the aging process. However, about 40% human life expectancy is inherited among generations, many lifespan associated genes, genetic mechanisms and pathways have been demonstrated during last decades. In the present review, we have evaluated many human genes and their non-human orthologs established for their role in the regulation of lifespan. The study has included more than fifty genes reported in the literature for their contributions to the longevity of life. Intact genomic DNA is essential for the life activities at the level of cell, tissue, and organ. Nucleic acids are vulnerable to oxidative stress, chemotherapies, and exposure to radiations. Efficient DNA repair mechanisms are essential for the maintenance of genomic integrity, damaged DNA is not replicated and transferred to next generations rather the presence of deleterious DNA initiates signaling cascades leading to the cell cycle arrest or apoptosis. DNA modifications, DNA methylation, histone methylation, histone acetylation and DNA damage can eventually lead towards apoptosis. The importance of calorie restriction therapy in the extension of lifespan has also been discussed. The role of pathways involved in the regulation of lifespan such as DAF-16/FOXO (forkhead box protein O1), TOR and JNK pathways has also been particularized. The study provides an updated account of genetic factors associated with the extended lifespan and their interactive contributory role with cellular pathways.
Collapse
Affiliation(s)
- May Nasser Bin-Jumah
- Biology Department, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia;
- Environment and Biomaterial Unit, Health Sciences Research Center, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia
| | - Muhammad Shahid Nadeem
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Sadaf Jamal Gilani
- Department of Basic Health Sciences, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia;
| | - Fahad A. Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Inam Ullah
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54000, Pakistan;
| | - Sami I. Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia;
| | - Mohammed M. Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia;
| | - Sultan Alshehri
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Aziz Uddin
- Department of Biotechnology and Genetic Engineering, Hazara University, Mansehra 21300, Pakistan;
| | - Bibi Nazia Murtaza
- Department of Zoology, Abbottabad University of Science and Technology (AUST), Abbottabad 22310, Pakistan;
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| |
Collapse
|
|
18
|
Therizols G, Bash-Imam Z, Panthu B, Machon C, Vincent A, Ripoll J, Nait-Slimane S, Chalabi-Dchar M, Gaucherot A, Garcia M, Laforêts F, Marcel V, Boubaker-Vitre J, Monet MA, Bouclier C, Vanbelle C, Souahlia G, Berthel E, Albaret MA, Mertani HC, Prudhomme M, Bertrand M, David A, Saurin JC, Bouvet P, Rivals E, Ohlmann T, Guitton J, Dalla Venezia N, Pannequin J, Catez F, Diaz JJ. Alteration of ribosome function upon 5-fluorouracil treatment favors cancer cell drug-tolerance. Nat Commun 2022; 13:173. [PMID: 35013311 PMCID: PMC8748862 DOI: 10.1038/s41467-021-27847-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5'-untranslated region. As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes.
Collapse
MESH Headings
- Antimetabolites, Antineoplastic/pharmacology
- Cell Line, Tumor
- Cell Survival/drug effects
- Colorectal Neoplasms/drug therapy
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/metabolism
- Colorectal Neoplasms/pathology
- DNA Replication
- DNA, Neoplasm/genetics
- DNA, Neoplasm/metabolism
- Drug Resistance, Neoplasm/genetics
- Drug Tolerance/genetics
- Fluorouracil/pharmacology
- HCT116 Cells
- Halogenation
- Humans
- Protein Biosynthesis/drug effects
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Ribosomal/genetics
- RNA, Ribosomal/metabolism
- Receptor, IGF Type 1/agonists
- Receptor, IGF Type 1/genetics
- Receptor, IGF Type 1/metabolism
- Ribosomes/drug effects
- Ribosomes/genetics
- Ribosomes/metabolism
- Xenograft Model Antitumor Assays
Collapse
Affiliation(s)
- Gabriel Therizols
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Zeina Bash-Imam
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Baptiste Panthu
- CIRI-Inserm U1111, Ecole Normale Supérieure de Lyon, Lyon, F-693643, France
- Inserm U1060, CARMEN, F-69310, Pierre Bénite, France
| | - Christelle Machon
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
- Laboratoire de chimie analytique, Faculté de pharmacie de Lyon, 8 avenue Rockefeller, F-69373, Lyon, France
- Laboratoire de biochimie et de pharmaco-toxicologie, Centre hospitalier Lyon-Sud - HCL, F-69495, Pierre Bénite, France
| | - Anne Vincent
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Julie Ripoll
- LIRMM, UMR 5506, University of Montpellier, CNRS, Montpellier, France
| | - Sophie Nait-Slimane
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Mounira Chalabi-Dchar
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Angéline Gaucherot
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Maxime Garcia
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Florian Laforêts
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Virginie Marcel
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | | | - Marie-Ambre Monet
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | | | - Christophe Vanbelle
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Guillaume Souahlia
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Elise Berthel
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Marie Alexandra Albaret
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
- Department of Translational Research and Innovation, Centre Léon Bérard, 69373, Lyon, France
| | - Hichem C Mertani
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Michel Prudhomme
- Department of Digestive Surgery, CHU Nimes, Univ Montpellier, Nimes, France
| | - Martin Bertrand
- Department of Digestive Surgery, CHU Nimes, Univ Montpellier, Nimes, France
| | - Alexandre David
- IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France
- IRMB-PPC, Univ Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France
| | - Jean-Christophe Saurin
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
- Department of Endoscopy and Gastroenterology, Pavillon L, Edouard Herriot Hospital, Lyon, France
| | - Philippe Bouvet
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
- Ecole Normale Supérieure de Lyon, Lyon, France
| | - Eric Rivals
- LIRMM, UMR 5506, University of Montpellier, CNRS, Montpellier, France
- Institut Français de Bioinformatique, CNRS UMS 3601, Évry, France
| | - Théophile Ohlmann
- CIRI-Inserm U1111, Ecole Normale Supérieure de Lyon, Lyon, F-693643, France
| | - Jérôme Guitton
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
- Laboratoire de biochimie et de pharmaco-toxicologie, Centre hospitalier Lyon-Sud - HCL, F-69495, Pierre Bénite, France
- Laboratoire de toxicologie, Faculté de pharmacie de Lyon, Université de Lyon, 8 avenue Rockefeller, F-69373, Lyon, France
| | - Nicole Dalla Venezia
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | | | - Frédéric Catez
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France.
- Centre Léon Bérard, F-69008, Lyon, France.
- Université de Lyon 1, F-69000, Lyon, France.
- Institut Convergence PLAsCAN, F-69373, Lyon, France.
| | - Jean-Jacques Diaz
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France.
- Centre Léon Bérard, F-69008, Lyon, France.
- Université de Lyon 1, F-69000, Lyon, France.
- Institut Convergence PLAsCAN, F-69373, Lyon, France.
| |
Collapse
|
|
19
|
Prekovic S, Schuurman K, Mayayo-Peralta I, Manjón AG, Buijs M, Yavuz S, Wellenstein MD, Barrera A, Monkhorst K, Huber A, Morris B, Lieftink C, Chalkiadakis T, Alkan F, Silva J, Győrffy B, Hoekman L, van den Broek B, Teunissen H, Debets DO, Severson T, Jonkers J, Reddy T, de Visser KE, Faller W, Beijersbergen R, Altelaar M, de Wit E, Medema R, Zwart W. Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer. Nat Commun 2021; 12:4360. [PMID: 34272384 PMCID: PMC8285479 DOI: 10.1038/s41467-021-24537-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 06/24/2021] [Indexed: 12/13/2022] Open
Abstract
The glucocorticoid receptor (GR) regulates gene expression, governing aspects of homeostasis, but is also involved in cancer. Pharmacological GR activation is frequently used to alleviate therapy-related side-effects. While prior studies have shown GR activation might also have anti-proliferative action on tumours, the underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the mechanisms of glucocorticoid response, focusing on lung cancer. We show that GR activation induces reversible cancer cell dormancy characterised by anticancer drug tolerance, and activation of growth factor survival signalling accompanied by vulnerability to inhibitors. GR-induced dormancy is dependent on a single GR-target gene, CDKN1C, regulated through chromatin looping of a GR-occupied upstream distal enhancer in a SWI/SNF-dependent fashion. These insights illustrate the importance of GR signalling in non-lymphoid solid cancer biology, particularly in lung cancer, and warrant caution for use of glucocorticoids in treatment of anticancer therapy related side-effects.
Collapse
Affiliation(s)
- Stefan Prekovic
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
| | - Karianne Schuurman
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Isabel Mayayo-Peralta
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Anna G Manjón
- Division of Cell Biology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Mark Buijs
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Selçuk Yavuz
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Max D Wellenstein
- Division of Tumour Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Alejandro Barrera
- Department of Biostatistics & Bioinformatics, and Centre for Genomic & Computational Biology, Duke University Medical Centre, Durham, NC, USA
| | - Kim Monkhorst
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Anne Huber
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia
| | - Ben Morris
- Division of Molecular Carcinogenesis and Robotics and Screening Centre, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Cor Lieftink
- Division of Molecular Carcinogenesis and Robotics and Screening Centre, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Theofilos Chalkiadakis
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ferhat Alkan
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Joana Silva
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Balázs Győrffy
- Semmelweis University Department of Bioinformatics and 2nd Department of Pediatrics, Budapest, Hungary.,TTK Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary
| | - Liesbeth Hoekman
- Mass spectrometry/Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Bram van den Broek
- Division of Cell Biology and BioImaging Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Hans Teunissen
- Division of Gene Regulation, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Donna O Debets
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Tesa Severson
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jos Jonkers
- Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Timothy Reddy
- Department of Biostatistics & Bioinformatics, and Centre for Genomic & Computational Biology, Duke University Medical Centre, Durham, NC, USA
| | - Karin E de Visser
- Division of Tumour Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - William Faller
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Roderick Beijersbergen
- Division of Molecular Carcinogenesis and Robotics and Screening Centre, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Maarten Altelaar
- Mass spectrometry/Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Elzo de Wit
- Division of Gene Regulation, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Rene Medema
- Division of Cell Biology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wilbert Zwart
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. .,Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
| |
Collapse
|
|
20
|
Kushiyama S, Yashiro M, Yamamoto Y, Sera T, Sugimoto A, Nishimura S, Togano S, Kuroda K, Yoshii M, Tamura T, Toyokawa T, Tanaka H, Muguruma K, Nakada H, Ohira M. Clinicopathologic significance of TROP2 and phospho-TROP2 in gastric cancer. Mol Clin Oncol 2021; 14:105. [PMID: 33815794 PMCID: PMC8010512 DOI: 10.3892/mco.2021.2267] [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: 08/28/2020] [Accepted: 01/19/2021] [Indexed: 01/04/2023] Open
Abstract
Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein expressed in epithelial cells. Increased TROP2 expression has been reported to be associated with malignant progression in most carcinomas; however, TROP2 has a tumor-suppressive function in certain types of cancer. Since the function of TROP2 is controversial, the present study subsequently aimed to clarify the clinicopathologic significance of TROP2 and pTROP2 expression in human gastric cancer (GC). The cases of 704 patients with GC who underwent gastrectomy were retrospectively analyzed. The expression levels of TROP2 and pTROP2 in each tumor were evaluated by immunohistochemistry. The association between the clinicopathologic features of patients with GC and the levels of TROP2 and pTROP2 in their tumors was analyzed. Increased TROP2 and pTROP2 expression was identified in 330 (46.9%) and 306 (43.5%) of the 704 patients with GC, respectively. Increased TROP2 expression was associated with the histological intestinal type, high tumor invasion depth (T3/T4), lymph node metastasis, lymphatic invasion and venous invasion. By contrast, increased pTROP2 expression was associated with intestinal type, low tumor invasion depth (T1/2), no lymph node metastasis and no lymphatic invasion. Increased TROP2 expression was associated with poorer overall survival (OS) (P<0.01; log rank test), whereas increased pTROP2 expression was significantly associated with improved OS (P<0.01; log rank test). In conclusion, increased expression levels of TROP2, but not pTROP2, may be associated with the metastatic ability of GC, resulting in poor prognosis of patients with GC.
Collapse
Affiliation(s)
- Shuhei Kushiyama
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Masakazu Yashiro
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Yurie Yamamoto
- Department of Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Tomohiro Sera
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Atsushi Sugimoto
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Sadaaki Nishimura
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Shingo Togano
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Kenji Kuroda
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Mami Yoshii
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Tatsuro Tamura
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Takahiro Toyokawa
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Hiroaki Tanaka
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Kazuya Muguruma
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Hiroshi Nakada
- Department of Molecular Biosciences, Faculty of Life Science, Kyoto Sangyo University, Kyoto 603-8555, Japan
| | - Masaichi Ohira
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| |
Collapse
|
|
21
|
Andrews DW, Judy KD, Scott CB, Garcia S, Harshyne LA, Kenyon L, Talekar K, Flanders A, Atsina KB, Kim L, Martinez N, Shi W, Werner-Wasik M, Liu H, Prosniak M, Curtis M, Kean R, Ye DY, Bongiorno E, Sauma S, Exley MA, Pigott K, Hooper DC. Phase Ib Clinical Trial of IGV-001 for Patients with Newly Diagnosed Glioblastoma. Clin Cancer Res 2021; 27:1912-1922. [PMID: 33500356 DOI: 10.1158/1078-0432.ccr-20-3805] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/23/2020] [Accepted: 01/14/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma. PATIENTS AND METHODS This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4-6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies. RESULTS Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001-treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall (n = 22; P = 0.001) and 17.1 months at the highest exposure (n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O6-methylguanine-DNA methyltransferase promoter (n = 10) demonstrated median PFS of 38.4 months (P = 0.0008). Evidence of immune activation was noted. CONCLUSIONS IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).
Collapse
Affiliation(s)
- David W Andrews
- Department of Neurological Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania. .,Imvax, Inc., Philadelphia, Pennsylvania
| | - Kevin D Judy
- Department of Neurological Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | | | - Samantha Garcia
- Department of Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Larry A Harshyne
- Department of Neurological Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Lawrence Kenyon
- Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Kiran Talekar
- Department of Neuroradiology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Adam Flanders
- Department of Neuroradiology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Kofi-Buaku Atsina
- Department of Neuroradiology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Lyndon Kim
- Mount Sinai Hospital, New York, New York
| | - Nina Martinez
- Department of Neurology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Wenyin Shi
- Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Maria Werner-Wasik
- Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Haisong Liu
- Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Mikhail Prosniak
- Department of Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Mark Curtis
- Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Rhonda Kean
- Department of Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Donald Y Ye
- Department of Neurological Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Emily Bongiorno
- Department of Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Sami Sauma
- Neuroscience Initiative, Advanced Science Research Center and Graduate Program in Biology, The Graduate Center at the City University of New York, New York, New York
| | | | | | - D Craig Hooper
- Department of Neurological Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.,Department of Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| |
Collapse
|
|
22
|
Baizig NM, Wided BA, Amine OE, Gritli S, ElMay M. The Clinical Significance of IGF-1R and Relationship with Epstein-Barr Virus Markers: LMP1 and EBERs in Tunisian Patients with Nasopharyngeal Carcinoma. Ann Otol Rhinol Laryngol 2020; 129:1011-1019. [PMID: 32468823 DOI: 10.1177/0003489420929362] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVES Tunisia is in the endemic area of nasopharyngeal carcinoma. Epstein-Barr virus (EBV) based assays have been commonly used as standard markers for screening and monitoring the disease. So, it is very important to find novel factors for the early diagnostic and prognostic evaluation of this cancer. The aim of the study was to evaluate the expression of IGF-1R (Insulin Growth Factor Receptor 1), LMP 1 (Latent Membrane Protein 1) and EBERs (EBV encoded RNAs) in order to determine their correlation with clinicopathologic parameters and survival rates in patients with nasopharyngeal carcinoma (NPC). We also looked for the relationship between these biomarkers. METHODS IGF-1R and LMP1 expression was performed by means of immunohistochemical method and EBERs were detected using in situ hybridization of paraffin embedded tumor tissues of 94 patients with nasopharyngeal carcinoma and 45 non-cancerous nasopharyngeal mucosa samples. RESULTS Our findings demonstrated that IGF-1R was over expressed in 47.87% of NPC patients and only in 2.22% of controls. Positive LMP1 expression was detected in 56.38% of NPC patients and all NPC patients were positive for the EBV-encoded RNAs staining. A statistically significant positive correlation was observed between IGF-1R expression and the tumor size (P < .001). Kaplan-Meier survival curves showed that NPC patients with a strong IGF-1R expression level have shorter median and 5-year Overall Survival than those with weak expression rates (100.15 vs 102.68 months, P = .08). In addition, median and 5-year Disease-Free Survival was significantly lower in the LMP1 positive NPC patients than in the LMP1 negative ones (53.38 vs 93.37 months, P = .03). Moreover, LMP1 expression correlated strongly with IGF-1R expression (P = .018). The relationship between these two biomarkers could influence patient survival. CONCLUSION IGF1-R and LMP1 could be valuable prognostic markers in Tunisian NPC patients.
Collapse
Affiliation(s)
- Nehla Mokni Baizig
- Immuno-Histo-Cytology Laboratory, Salah Azaiz Cancer Institute, Tunis, Tunisia
| | - Ben Ayoub Wided
- Department of statistics and medical informatics, Salah Azaiz Cancer Institute, Tunis, Tunisia
| | - Olfa El Amine
- Immuno-Histo-Cytology Laboratory, Salah Azaiz Cancer Institute, Tunis, Tunisia
| | - Said Gritli
- ENT Department, Salah Azaiz Cancer Institute, Tunis, Tunisia
| | - Michele ElMay
- Research Unit 17/ ES/13, Faculty of Medicine, Tunis, University of Tunis El Manar, Tunisia
| |
Collapse
|
|
23
|
Wang C, Wang S, Liu S, Cheng Y, Geng H, Yang R, Feng T, Lu G, Sun X, Song J, Hao L. Synonymous Mutations of Porcine Igf1r Extracellular Domain Affect Differentiation and Mineralization in MC3T3-E1 Cells. Front Cell Dev Biol 2020; 8:623. [PMID: 32754602 PMCID: PMC7381325 DOI: 10.3389/fcell.2020.00623] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 06/22/2020] [Indexed: 12/27/2022] Open
Abstract
Owing to the wide application of miniature pigs in biomedicine, the formation mechanism of its short stature must be elucidated. The insulin-like growth factor 1 receptor (IGF-1R), which receives signals through the extracellular domain (ECD) binding with ligands, is crucial in regulating cell growth and bone matrix mineralization. In this study, two haplotypes of Igf1r with four synonymous mutations in the coding sequences of IGF-1R ECD between large pigs (LP) and Bama pigs (BM) were stably expressed in the Igf1r-knockout MC3T3-E1 cells and named as MC3T3-LP cells (LP group) and MC3T3-BM cells (BM group), respectively. IGF-1R expression was lower in the BM group than in the LP group both in terms of transcription and translation levels, and IGF-1R expression inhibited cell proliferation. In addition, IGF-1R expression in the BM group promoted early-stage differentiation but delayed late-stage differentiation, which not only suppressed the expression of bone-related factors but also reduced alkaline phosphatase activity and calcium deposition. Moreover, different haplotypes of Igf1r changed the stability and conformation of the protein, further affecting the binding with IGF-1. Our data indicated that the four synonymous mutations of IGF1R ECD encoded by affect gene transcription and translation, thereby further leading to differences in the downstream pathways and functional changes of osteoblasts.
Collapse
Affiliation(s)
- Chunli Wang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Siyao Wang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Songcai Liu
- College of Animal Sciences, Jilin University, Changchun, China
| | - Yunyun Cheng
- College of Animal Sciences, Jilin University, Changchun, China
| | - Hongwei Geng
- College of Animal Sciences, Jilin University, Changchun, China
| | - Rui Yang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Tianqi Feng
- College of Animal Sciences, Jilin University, Changchun, China
| | - Guanhong Lu
- College of Animal Sciences, Jilin University, Changchun, China
| | - Xiaotong Sun
- College of Animal Sciences, Jilin University, Changchun, China
| | - Jie Song
- College of Animal Sciences, Jilin University, Changchun, China
| | - Linlin Hao
- College of Animal Sciences, Jilin University, Changchun, China
| |
Collapse
|
|
24
|
Zhang M, Lin B, Liu Y, Huang T, Chen M, Lian D, Deng S, Zhuang C. LINC00324 affects non-small cell lung cancer cell proliferation and invasion through regulation of the miR-139-5p/IGF1R axis. Mol Cell Biochem 2020; 473:193-202. [PMID: 32734536 DOI: 10.1007/s11010-020-03819-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 06/27/2020] [Indexed: 01/02/2023]
Abstract
Long non-coding RNAs (lncRNAs) are proved to perform critical function in regulating cancer cell behavior. It is reported that LINC00324 promotes lung adenocarcinoma development by regulating miR-615-5p/AKT1 axis. This study aimed to demonstrate whether LINC00324 participates in non-small cell lung cancer (NSCLC) pathogenesis through other molecular mechanism. Relative mRNA, lncRNA, and microRNA levels were analyzed using quantitative real-time-polymerase chain reaction (qRT-PCR). Western blot was used to detect protein level. MTT assay shown proliferation ability and transwell assay shown invasive ability. Luciferase reporter assay illustrated the interaction between RNA molecules. In NSCLC, the high expression of LINC00324 had correlation with the poor prognosis. LINC00324 promoted the proliferation and invasion of NSCLC cells while miR-139-5p inhibited these behaviors. LINC00324 overexpression promoted insulin-like growth factor 1 receptor (IGF1R) expression via absorbing miR-139-5p. The tumor-promoting effects of LINC00324 were attenuated through miR-139-5p overexpression. Highly expressed LINC00324 in NSCLC through sponged miR-139-5p to elevate IGF1R expression and promoted cell proliferation and invasion. This research demonstrated that LINC00324 is a potential NSCLC diagnosis and therapy target.
Collapse
Affiliation(s)
- Meiqing Zhang
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China
| | - Baoquan Lin
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China
| | - Yaming Liu
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China
| | - Tengfei Huang
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China
| | - Mengmeng Chen
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China
| | - Duohuang Lian
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China
| | - Shilong Deng
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China
| | - Congwen Zhuang
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China.
| |
Collapse
|
|
25
|
Sohrabi M, Floden AM, Manocha GD, Klug MG, Combs CK. IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer's Disease Transgenic Mouse Model. Front Cell Neurosci 2020; 14:200. [PMID: 32719587 PMCID: PMC7348663 DOI: 10.3389/fncel.2020.00200] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 06/08/2020] [Indexed: 01/01/2023] Open
Abstract
Aging is a major risk factor for Alzheimer's disease (AD). Insulin-like growth factor-1 receptor (IGF-1R) regulates general aging and lifespan. However, the contribution of IGF-1 to age-related AD pathology and progression is highly controversial. Based on our previous work, AβPP/PS1 double transgenic mice, which express human mutant amyloid precursor protein (APP) and presenilin-1 (PS-1), demonstrated a decrease in brain IGF-1 levels when they were crossed with IGF-1 deficient Ames dwarf mice (df/df). Subsequently, a reduction in gliosis, amyloid-β (Aβ) plaque deposition, and Aβ1-40/42 concentrations were observed in this mouse model. This supported the hypothesis that IGF-1 may contribute to the progression of the disease. To assess the role of IGF-1 in AD, 9-10-month-old male littermate control wild type and AβPP/PS1 mice were randomly divided into two treatment groups including control vehicle (DMSO) and picropodophyllin (PPP), a selective, competitive, and reversible IGF-1R inhibitor. The brain penetrant inhibitor was given ip. at 1 mg/kg/day. Mice were sacrificed after 7 days of daily injection and the brains, spleens, and livers were collected to quantify histologic and biochemical changes. The PPP-treated AβPP/PS1 mice demonstrated attenuated insoluble Aβ1-40/42. Additionally, an attenuation in microgliosis and protein p-tyrosine levels was observed due to drug treatment in the hippocampus. Our data suggest IGF-1R signaling is associated with disease progression in this mouse model. More importantly, modulation of the brain IGF-1R signaling pathway, even at mid-life, was enough to attenuate aspects of the disease phenotype. This suggests that small molecule therapy targeting the IGF-1R pathway may be viable for late-stage disease treatment.
Collapse
Affiliation(s)
- Mona Sohrabi
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States
| | - Angela M Floden
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States
| | - Gunjan D Manocha
- Department of Geriatrics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States
| | - Marilyn G Klug
- Department of Population Health, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States
| | - Colin K Combs
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States
| |
Collapse
|
|
26
|
Ben Elhadj M, Goucha A, Fourati A, Adouni O, Dhambri S, Hsairi M, El May MV, Mokni Baizig N. The Prognostic Significance of IGF-1R and the Predictive Risk Value of Circulating IGF-1 in Tunisian Patients with Laryngeal Carcinoma. Cancer Invest 2020; 38:289-299. [PMID: 32308049 DOI: 10.1080/07357907.2020.1758711] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The aim was to evaluate the clinical impact of IGF-1/IGF-1R in Tunisian laryngeal carcinoma. A high IGF-1R immunohistochemical expression was found in our series (81.43%). A tendency toward an association between IGF-1R expression and lymph node metastasis was found (p = 0.068). Patients with positive IGF-1R expression showed a short disease free survival (p = 0.053) and a high recurrence rate. Furthermore, circulating IGF-1 levels sera, detected by ELISA, were higher among patients compared to controls (p < 0.001). IGF-1R might have a prognostic significance and could be a factor of tumor recurrence. However, high levels of IGF-1 increase the risk of developing of LSCC disease.
Collapse
Affiliation(s)
- Mariem Ben Elhadj
- Departement of Immuno-Histo-Cytology, Salah Azaiez Cancer Institute, Tunis, Tunisia.,Research unit 17/ES/13 Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
| | - Aida Goucha
- Departement of Immuno-Histo-Cytology, Salah Azaiez Cancer Institute, Tunis, Tunisia
| | - Asma Fourati
- Departement of Immuno-Histo-Cytology, Salah Azaiez Cancer Institute, Tunis, Tunisia.,Research unit 17/ES/13 Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
| | - Olfa Adouni
- Departement of Immuno-Histo-Cytology, Salah Azaiez Cancer Institute, Tunis, Tunisia
| | - Sawsen Dhambri
- Departement of ORL, Salah Azaiez Cancer Institute, Tunis, Tunisia
| | - Mohamed Hsairi
- Departement of Epidemiology, Salah Azaiez Cancer Institute, Tunis, Tunisia
| | | | - Nehla Mokni Baizig
- Departement of Immuno-Histo-Cytology, Salah Azaiez Cancer Institute, Tunis, Tunisia.,Research unit 17/ES/13 Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
| |
Collapse
|
|
27
|
Dhadve AC, Hari K, Rekhi B, Jolly MK, De A, Ray P. Decoding molecular interplay between RUNX1 and FOXO3a underlying the pulsatile IGF1R expression during acquirement of chemoresistance. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165754. [PMID: 32142859 DOI: 10.1016/j.bbadis.2020.165754] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 02/11/2020] [Accepted: 02/28/2020] [Indexed: 12/17/2022]
Abstract
Hyperactive Insulin like growth factor-1-receptor (IGF1R) signalling is associated with development of therapy resistance in many cancers. We recently reported a pulsatile nature of IGF1R during acquirement of platinum-taxol resistance in Epithelial Ovarian Cancer (EOC) cells and a therapy induced upregulation in IGF1R expression in tumors of a small cohort of high grade serous EOC patients. Here, we report Runt-related transcription factor 1 (RUNX1) as a novel transcriptional regulator which along with another known regulator Forkhead Box O3 (FOXO3a), drives the dynamic modulation of IGF1R expression during platinum-taxol resistance development in EOC cells. RUNX1-FOXO3a cooperatively bind to IGF1R promoter and produce a transcriptional surge during onset of resistance and such co-operativity falls apart when cells attain maximal resistance resulting in decreased IGF1R expression. The intriguing descending trend in IGF1R and FOXO3a expressions is caused by a Protein Kinase B (AKT)-FOXO3a negative feedback loop exclusively present in the highly resistant cells eliciting the pulsatile behaviour of IGF1R and FOXO3a. In vivo molecular imaging revealed that RUNX1 inhibition causes significant attenuation of the IGF1R promoter activity, decreased tumorigenicity and enhanced drug sensitivity of tumors of early resistant cells. Altogether our findings delineate a dynamic interplay between several molecular regulators driving pulsatile IGF1R expression and identify a new avenue for targeting EOC through RUNX1-IGF1R axis during acquirement of chemoresistance.
Collapse
Affiliation(s)
- Ajit C Dhadve
- Imaging Cell Signaling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai, India
| | - Kishore Hari
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India
| | - Bharat Rekhi
- Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, India
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India
| | - Abhijit De
- Molecular Functional Imaging Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai, India
| | - Pritha Ray
- Imaging Cell Signaling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai, India.
| |
Collapse
|
|
28
|
Kowalczyk A, Partha R, Clark NL, Chikina M. Pan-mammalian analysis of molecular constraints underlying extended lifespan. eLife 2020; 9:e51089. [PMID: 32043462 PMCID: PMC7012612 DOI: 10.7554/elife.51089] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 01/14/2020] [Indexed: 12/23/2022] Open
Abstract
Although lifespan in mammals varies over 100-fold, the precise evolutionary mechanisms underlying variation in longevity remain unknown. Species-specific genetic changes have been observed in long-lived species including the naked mole-rat, bats, and the bowhead whale, but these adaptations do not generalize to other mammals. We present a novel method to identify associations between rates of protein evolution and continuous phenotypes across the entire mammalian phylogeny. Unlike previous analyses that focused on individual species, we treat absolute and relative longevity as quantitative traits and demonstrate that these lifespan traits affect the evolutionary constraint on hundreds of genes. Specifically, we find that genes related to cell cycle, DNA repair, cell death, the IGF1 pathway, and immunity are under increased evolutionary constraint in large and long-lived mammals. For mammals exceptionally long-lived for their body size, we find increased constraint in inflammation, DNA repair, and NFKB-related pathways. Strikingly, these pathways have considerable overlap with those that have been previously reported to have potentially adaptive changes in single-species studies, and thus would be expected to show decreased constraint in our analysis. This unexpected finding of increased constraint in many longevity-associated pathways underscores the power of our quantitative approach to detect patterns that generalize across the mammalian phylogeny.
Collapse
Affiliation(s)
- Amanda Kowalczyk
- Joint Carnegie Mellon University-University of Pittsburgh PhD Program in Computational BiologyPittsburghUnited States
- Department of Computational and Systems BiologyUniversity of PittsburghPittsburghUnited States
| | - Raghavendran Partha
- Joint Carnegie Mellon University-University of Pittsburgh PhD Program in Computational BiologyPittsburghUnited States
- Department of Computational and Systems BiologyUniversity of PittsburghPittsburghUnited States
| | - Nathan L Clark
- Department of Computational and Systems BiologyUniversity of PittsburghPittsburghUnited States
- Pittsburgh Center for Evolutionary Biology and MedicineUniversity of PittsburghPittsburghUnited States
- Department of Human GeneticsUniversity of UtahSalt Lake CityUnited States
| | - Maria Chikina
- Department of Computational and Systems BiologyUniversity of PittsburghPittsburghUnited States
| |
Collapse
|
|
29
|
Molina ER, Chim LK, Salazar MC, Mehta SM, Menegaz BA, Lamhamedi-Cherradi SE, Satish T, Mohiuddin S, McCall D, Zaske AM, Cuglievan B, Lazar AJ, Scott DW, Grande-Allen JK, Ludwig JA, Mikos AG. Mechanically tunable coaxial electrospun models of YAP/TAZ mechanoresponse and IGF-1R activation in osteosarcoma. Acta Biomater 2019; 100:38-51. [PMID: 31542501 PMCID: PMC7027943 DOI: 10.1016/j.actbio.2019.09.029] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 08/29/2019] [Accepted: 09/17/2019] [Indexed: 01/08/2023]
Abstract
Current in vitro methods for assessing cancer biology and therapeutic response rely heavily on monolayer cell culture on hard, plastic surfaces that do not recapitulate essential elements of the tumor microenvironment. While a host of tumor models exist, most are not engineered to control the physical properties of the microenvironment and thus may not reflect the effects of mechanotransduction on tumor biology. Utilizing coaxial electrospinning, we developed three-dimensional (3D) tumor models with tunable mechanical properties in order to elucidate the effects of substrate stiffness and tissue architecture in osteosarcoma. Mechanical properties of coaxial electrospun meshes were characterized with a series of macroscale testing with uniaxial tensile testing and microscale testing utilizing atomic force microscopy on single fibers. Calculated moduli in our models ranged over three orders of magnitude in both macroscale and microscale testing. Osteosarcoma cells responded to decreasing substrate stiffness in 3D environments by increasing nuclear localization of Hippo pathway effectors, YAP and TAZ, while downregulating total YAP. Additionally, a downregulation of the IGF-1R/mTOR axis, the target of recent clinical trials in sarcoma, was observed in 3D models and heralded increased resistance to combination chemotherapy and IGF-1R/mTOR targeted agents compared to monolayer controls. In this study, we highlight the necessity of incorporating mechanical cues in cancer biology investigation and the complexity in mechanotransduction as a confluence of stiffness and culture architecture. Our models provide a versatile, mechanically variable substrate on which to study the effects of physical cues on the pathogenesis of tumors. STATEMENT OF SIGNIFICANCE: The tumor microenvironment plays a critical role in cancer pathogenesis. In this work, we engineered 3D, mechanically tunable, coaxial electrospun environments to determine the roles of the mechanical environment on osteosarcoma cell phenotype, morphology, and therapeutic response. We characterize the effects of varying macroscale and microscale stiffnesses in 3D environments on the localization and expression of the mechanoresponsive proteins, YAP and TAZ, and evaluate IGF-1R/mTOR pathway activation, a target of recent clinical trials in sarcoma. Increased nuclear YAP/TAZ was observed as stiffness in 3D was decreased. Downregulation of the IGF-1R/mTOR cascade in all 3D environments was observed. Our study highlights the complexity of mechanotransduction in 3D culture and represents a step towards controlling microenvironmental elements in in vitro cancer investigations.
Collapse
Affiliation(s)
- Eric R Molina
- Department of Bioengineering, Rice University, Houston, TX, United States
| | - Letitia K Chim
- Department of Bioengineering, Rice University, Houston, TX, United States
| | - Maria C Salazar
- Department of Bioengineering, Rice University, Houston, TX, United States
| | - Shail M Mehta
- Department of Applied Physics, Rice University, Houston, TX, United States
| | - Brian A Menegaz
- Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, United States
| | - Salah-Eddine Lamhamedi-Cherradi
- Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, United States
| | - Tejus Satish
- Department of Bioengineering, Rice University, Houston, TX, United States
| | - Sana Mohiuddin
- Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, United States
| | - David McCall
- Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, United States
| | - Ana Maria Zaske
- The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Branko Cuglievan
- Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, United States
| | - Alexander J Lazar
- Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, United States; Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, United States
| | - David W Scott
- Department of Statistics, Rice University, Houston, TX, United States
| | | | - Joseph A Ludwig
- Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, United States
| | - Antonios G Mikos
- Department of Bioengineering, Rice University, Houston, TX, United States.
| |
Collapse
|
|
30
|
Crudden C, Song D, Cismas S, Trocmé E, Pasca S, Calin GA, Girnita A, Girnita L. Below the Surface: IGF-1R Therapeutic Targeting and Its Endocytic Journey. Cells 2019; 8:cells8101223. [PMID: 31600876 PMCID: PMC6829878 DOI: 10.3390/cells8101223] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 09/30/2019] [Accepted: 10/03/2019] [Indexed: 12/15/2022] Open
Abstract
Ligand-activated plasma membrane receptors follow pathways of endocytosis through the endosomal sorting apparatus. Receptors cluster in clathrin-coated pits that bud inwards and enter the cell as clathrin-coated vesicles. These vesicles travel through the acidic endosome whereby receptors and ligands are sorted to be either recycled or degraded. The traditional paradigm postulated that the endocytosis role lay in signal termination through the removal of the receptor from the cell surface. It is now becoming clear that the internalization process governs more than receptor signal cessation and instead reigns over the entire spatial and temporal wiring of receptor signaling. Governing the localization, the post-translational modifications, and the scaffolding of receptors and downstream signal components established the endosomal platform as the master regulator of receptor function. Confinement of components within or between distinct organelles means that the endosome instructs the cell on how to interpret and translate the signal emanating from any given receptor complex into biological effects. This review explores this emerging paradigm with respect to the cancer-relevant insulin-like growth factor type 1 receptor (IGF-1R) and discusses how this perspective could inform future targeting strategies.
Collapse
Affiliation(s)
- Caitrin Crudden
- Department of Oncology-Pathology, Cellular and Molecular Tumor Pathology, Karolinska Institute, and Karolinska University Hospital, 17164 Stockholm, Sweden.
- Department of Pathology, Cancer Centre Amsterdam, Amsterdam UMC, VU University Medical Centre, 1081 HZ Amsterdam, The Netherlands.
| | - Dawei Song
- Department of Oncology-Pathology, Cellular and Molecular Tumor Pathology, Karolinska Institute, and Karolinska University Hospital, 17164 Stockholm, Sweden.
| | - Sonia Cismas
- Department of Oncology-Pathology, Cellular and Molecular Tumor Pathology, Karolinska Institute, and Karolinska University Hospital, 17164 Stockholm, Sweden.
| | - Eric Trocmé
- Department of Oncology-Pathology, Cellular and Molecular Tumor Pathology, Karolinska Institute, and Karolinska University Hospital, 17164 Stockholm, Sweden.
- St. Erik Eye Hospital, 11282 Stockholm, Sweden.
| | - Sylvya Pasca
- Department of Oncology-Pathology, Cellular and Molecular Tumor Pathology, Karolinska Institute, and Karolinska University Hospital, 17164 Stockholm, Sweden.
| | - George A Calin
- Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Ada Girnita
- Department of Oncology-Pathology, Cellular and Molecular Tumor Pathology, Karolinska Institute, and Karolinska University Hospital, 17164 Stockholm, Sweden.
- Dermatology Department, Karolinska University Hospital, 17176 Stockholm, Sweden.
| | - Leonard Girnita
- Department of Oncology-Pathology, Cellular and Molecular Tumor Pathology, Karolinska Institute, and Karolinska University Hospital, 17164 Stockholm, Sweden.
| |
Collapse
|
|
31
|
Erickson KE, Rukhlenko OS, Shahinuzzaman M, Slavkova KP, Lin YT, Suderman R, Stites EC, Anghel M, Posner RG, Barua D, Kholodenko BN, Hlavacek WS. Modeling cell line-specific recruitment of signaling proteins to the insulin-like growth factor 1 receptor. PLoS Comput Biol 2019; 15:e1006706. [PMID: 30653502 PMCID: PMC6353226 DOI: 10.1371/journal.pcbi.1006706] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 01/30/2019] [Accepted: 12/09/2018] [Indexed: 12/27/2022] Open
Abstract
Receptor tyrosine kinases (RTKs) typically contain multiple autophosphorylation sites in their cytoplasmic domains. Once activated, these autophosphorylation sites can recruit downstream signaling proteins containing Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains, which recognize phosphotyrosine-containing short linear motifs (SLiMs). These domains and SLiMs have polyspecific or promiscuous binding activities. Thus, multiple signaling proteins may compete for binding to a common SLiM and vice versa. To investigate the effects of competition on RTK signaling, we used a rule-based modeling approach to develop and analyze models for ligand-induced recruitment of SH2/PTB domain-containing proteins to autophosphorylation sites in the insulin-like growth factor 1 (IGF1) receptor (IGF1R). Models were parameterized using published datasets reporting protein copy numbers and site-specific binding affinities. Simulations were facilitated by a novel application of model restructuration, to reduce redundancy in rule-derived equations. We compare predictions obtained via numerical simulation of the model to those obtained through simple prediction methods, such as through an analytical approximation, or ranking by copy number and/or KD value, and find that the simple methods are unable to recapitulate the predictions of numerical simulations. We created 45 cell line-specific models that demonstrate how early events in IGF1R signaling depend on the protein abundance profile of a cell. Simulations, facilitated by model restructuration, identified pairs of IGF1R binding partners that are recruited in anti-correlated and correlated fashions, despite no inclusion of cooperativity in our models. This work shows that the outcome of competition depends on the physicochemical parameters that characterize pairwise interactions, as well as network properties, including network connectivity and the relative abundances of competitors. Cells rely on networks of interacting biomolecules to sense and respond to environmental perturbations and signals. However, it is unclear how information is processed to generate appropriate and specific responses to signals, especially given that these networks tend to share many components. For example, receptors that detect distinct ligands and regulate distinct cellular activities commonly interact with overlapping sets of downstream signaling proteins. Here, to investigate the downstream signaling of a well-studied receptor tyrosine kinase (RTK), the insulin-like growth factor 1 (IGF1) receptor (IGF1R), we formulated and analyzed 45 cell line-specific mathematical models, which account for recruitment of 18 different binding partners to six sites of receptor autophosphorylation in IGF1R. The models were parameterized using available protein copy number and site-specific affinity measurements, and restructured to allow for network generation. We find that recruitment is influenced by the protein abundance profile of a cell, with different patterns of recruitment in different cell lines. Furthermore, in a given cell line, we find that pairs of IGF1R binding partners may be recruited in a correlated or anti-correlated fashion. We demonstrate that the simulations of the model have greater predictive power than protein copy number and/or binding affinity data, and that even a simple analytical model cannot reproduce the predicted recruitment ranking obtained via simulations. These findings represent testable predictions and indicate that the outputs of IGF1R signaling depend on cell line-specific properties in addition to the properties that are intrinsic to the biomolecules involved.
Collapse
Affiliation(s)
- Keesha E. Erickson
- Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
| | | | - Md Shahinuzzaman
- Department of Chemical and Biochemical Engineering, University of Missouri Science and Technology, Rolla, Missouri, United States of America
| | - Kalina P. Slavkova
- Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
- Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
| | - Yen Ting Lin
- Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
- Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
| | - Ryan Suderman
- Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
- Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
| | - Edward C. Stites
- The Salk Institute for Biological Studies, La Jolla, California, United States of America
| | - Marian Anghel
- Information Sciences Group, Computer, Computational and Statistical Sciences Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
| | - Richard G. Posner
- Department of Biological Sciences, Northern Arizona University, Flagstaff, Arizona, United States of America
| | - Dipak Barua
- Department of Chemical and Biochemical Engineering, University of Missouri Science and Technology, Rolla, Missouri, United States of America
| | - Boris N. Kholodenko
- Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland
- School of Medicine and Medical Science and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
| | - William S. Hlavacek
- Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
- Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
- * E-mail:
| |
Collapse
|
|
32
|
Vlahovic G, Meadows KL, Hatch AJ, Jia J, Nixon AB, Uronis HE, Morse MA, Selim MA, Crawford J, Riedel RF, Zafar SY, Howard LA, O'Neill M, Meadows JJ, Haley ST, Arrowood CC, Rushing C, Pang H, Hurwitz HI. A Phase I Trial of the IGF-1R Antibody Ganitumab (AMG 479) in Combination with Everolimus (RAD001) and Panitumumab in Patients with Advanced Cancer. Oncologist 2018; 23:782-790. [PMID: 29572245 DOI: 10.1634/theoncologist.2016-0377] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 08/17/2017] [Indexed: 11/17/2022] Open
Abstract
PURPOSE This study evaluated the maximum tolerated dose or recommended phase II dose (RPTD) and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. MATERIALS AND METHODS This was a standard 3 + 3 dose escalation trial. Doublet therapy consisted of ganitumab at 12 mg/kg every 2 weeks; doses of everolimus were adjusted according to dose-limiting toxicities (DLTs). Panitumumab at 4.8 mg/kg every 2 weeks was added to the RPTD of ganitumab and everolimus. DLTs were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Pretreatment and on-treatment skin biopsies were collected to assess insulin-like growth factor 1 receptor and mammalian target of rapamycin (mTOR) target modulation. RESULTS Forty-three subjects were enrolled. In the doublet regimen, two DLTs were observed in cohort 1, no DLTs in cohort -1, and one in cohort -1B. The triplet combination was discontinued because of unacceptable toxicity. Common adverse events were thrombocytopenia/neutropenia, skin rash, mucositis, fatigue, and hyperglycemia. In the doublet regimen, two patients with refractory non-small cell lung cancer (NSCLC) achieved prolonged complete responses ranging from 18 to >60 months; one treatment-naïve patient with chondrosarcoma achieved prolonged stable disease >24 months. In dermal granulation tissue, the insulin-like growth factor receptor and mTOR pathways were potently and specifically inhibited by ganitumab and everolimus, respectively. CONCLUSION The triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity. However, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory NSCLC and sarcoma. IMPLICATIONS FOR PRACTICE This trial evaluated the maximum tolerated dose or recommended phase II dose and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. Although the triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus at five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory non-small cell lung cancer and sarcoma.
Collapse
Affiliation(s)
| | | | - Ace J Hatch
- Duke Cancer Institute, Durham, North Carolina, USA
| | - Jingquan Jia
- Duke Cancer Institute, Durham, North Carolina, USA
| | | | | | | | - M Angelica Selim
- Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA
| | | | | | | | | | | | | | | | | | | | - Herbert Pang
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, USA
| | | |
Collapse
|
|
33
|
Abstract
Several substances such as growth hormone (GH), erythropoietin (Epo), and anabolic steroids (AS) are improperly utilized to increase the performance of athletes. Evaluating the potential cancer risk associated with doping agents is difficult since these drugs are often used at very high doses and in combination with other licit or illicit drugs. The GH, via its mediator, the insulin-like growth factor 1 (IGF-1), is involved in the development and progression of cancer. Animal studies suggested that high levels of GH/IGF-1 increase progression of androgen-independent prostate cancer. Clinical data regarding prostate cancer are mostly based on epidemiological studies or indirect data such as IGF-1 high levels in patients with prostate cancer. Even if experimental studies showed a correlation between Epo and cancer, no clinical data are currently available on cancer development related to Epo as a doping agent. Androgens are involved in prostate carcinogenesis modulating genes that regulate cell proliferation, apoptosis and angiogenesis. Most information on AS is anecdotal (case reports on prostate, kidney and testicular cancers). Prospective epidemiologic studies failed to support the hypothesis that circulating androgens are positively associated with prostate cancer risk. Currently, clinical and epidemiological studies supporting association between doping and urological neoplasias are not available. Nowadays, exposure to doping agents starts more prematurely with a consequent longer exposition period; drugs are often used at very high doses and in combination with other licit or illicit drugs. Due to all these elements it is impossible to predict all the side effects, including cancer; more detailed studies are therefore necessary.
Collapse
|
|
34
|
Functional antagonism of β-arrestin isoforms balance IGF-1R expression and signalling with distinct cancer-related biological outcomes. Oncogene 2017; 36:5734-5744. [PMID: 28581517 PMCID: PMC5658667 DOI: 10.1038/onc.2017.179] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 04/09/2017] [Accepted: 05/01/2017] [Indexed: 12/21/2022]
Abstract
With very similar 3D structures, the widely expressed β-arrestin isoforms 1 and 2 play at times identical, distinct or even opposing roles in regulating various aspects of G protein-coupled receptors (GPCR) expression and signalling. Recent evidence recognizes the β-arrestin system as a key regulator of not only GPCRs, but also receptor tyrosine kinases, including the highly cancer relevant insulin-like growth factor type 1 receptor (IGF-1R). Binding of β-arrestin1 to IGF-1R leads to ligand-dependent degradation of the receptor and generates additional MAPK/ERK signalling, protecting cancer cells against anti-IGF-1R therapy. Because the interplay between β-arrestin isoforms governs the biological effects for most GPCRs, as yet unexplored for the IGF-1R, we sought to investigate specifically the regulatory roles of the β-arrestin2 isoform on expression and function of the IGF-1R. Results from controlled expression of either β-arrestin isoform demonstrate that β-arrestin2 acts in an opposite manner to β-arrestin1 by promoting degradation of an unstimulated IGF-1R, but protecting the receptor against agonist-induced degradation. Although both isoforms co-immunoprecipitate with IGF-1R, the ligand-occupied receptor has greater affinity for β-arrestin1; this association lasts longer, sustains MAPK/ERK signalling and mitigates p53 activation. Conversely, β-arrestin2 has greater affinity for the ligand-unoccupied receptor; this interaction is transient, triggers receptor ubiquitination and degradation without signalling activation, and leads to a lack of responsiveness to IGF-1, cell cycle arrest and decreased viability of cancer cells. This study reveals contrasting abilities of IGF-1R to interact with each β-arrestin isoform, depending on the presence of the ligand and demonstrates the antagonism between the two β-arrestin isoforms in controlling IGF-1R expression and function, which could be developed into a practical anti-IGF-1R strategy for cancer therapy.
Collapse
|
|
35
|
Gong H, Wang X, Wang L, Liu Y, Wang J, Lv Q, Pang H, Zhang Q, Wang Z. Inhibition of IGF-1 receptor kinase blocks the differentiation into cardiomyocyte-like cells of BMSCs induced by IGF-1. Mol Med Rep 2017; 16:787-793. [PMID: 28560388 PMCID: PMC5482190 DOI: 10.3892/mmr.2017.6639] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 03/21/2017] [Indexed: 01/18/2023] Open
Abstract
Bone marrow mesenchymal stem cells (BMSCs) have the potential to transdifferentiate into cardiomyocyte-like cells (CLCs) if an appropriate cardiac environment is provided. Insulin-like growth factor-1 (IGF-1) plays an important role in the cell migration, survival and differentiation of BMSCs. However, the effect of IGF-1 on the cellular differentiation remains unclear. In the present study, BMSCs were isolated from rat femurs and tibias and the cells were purified at passage 6 (P6). IGF-1 and IGF-1 receptor (IGF-1R) kinase inhibitor I-OMe AG538 were added to detect if IGF-1 could induce BMSCs to transdifferentiate into CLCs and if I-OMe AG538 could inhibit IGF-1-mediated receptor activation and downstream signaling. Immunostaining demonstrated that all P6 BMSCs express CD29 and CD44 but not CD45. BMSCs induced by 15 ng/ml IGF-1 revealed positivity for cardiac troponin-T and cardiac troponin-I. The optimal induction time was 14 days but the expression of these proteins were incompletely inhibited by 300 nmol/l I-OMe AG538 and completely inhibited by 10 µmol/l I-OMe AG538. Western blotting showed that the level of IGF-1R autophosphorylation and the expression of cTnT and cTnI were higher when BMSCs were induced for 14 days. I-OMe AG538 selectively inhibited IGF-1-mediated growth and signal transduction and the inhibitory effect of I-OMe AG538 were not reverted in the presence of exogenous IGF-1. In addition, when a time course analysis of the effects of I-OMe AG538 on mitogen-activated protein kinase kinase and phosphatidylinositol 3-kinase signaling were done, we observed a transient inhibitory effect on Erk1/2 and Akt phosphorylation, in keeping with the inhibitory effects on cell growth. Taken together, these data indicate that I-OMe AG538 could inhibit IGF-1-induced CLCs in BMSCs and this effect is time- and concentration-dependent.
Collapse
Affiliation(s)
- Haibin Gong
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Xiuli Wang
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Lei Wang
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Ying Liu
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Jie Wang
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Qian Lv
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Hui Pang
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Qinglin Zhang
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Zhenquan Wang
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| |
Collapse
|
|
36
|
Snail-Modulated MicroRNA 493 Forms a Negative Feedback Loop with the Insulin-Like Growth Factor 1 Receptor Pathway and Blocks Tumorigenesis. Mol Cell Biol 2017; 37:MCB.00510-16. [PMID: 27956702 DOI: 10.1128/mcb.00510-16] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 12/06/2016] [Indexed: 12/15/2022] Open
Abstract
In this study, we have identified one microRNA, microRNA 493 (miR-493), which could simultaneously and directly regulate multiple genes downstream of the insulin-like growth factor 1 receptor (IGF1R) pathway, including IGF1R, by binding with complementary sequences in the 3' untranslated region (UTR) of mRNAs of IGF1R, insulin receptor substrate 1 (IRS1), and mitogen-activated protein kinase 1 (MAPK1), thereby potentiating their inhibitory function at multiple levels in development and progression of cancers. This binding was further confirmed by pulldown of miR with AGO-2 antibody. Further, results from head and neck samples showed that miR-493 levels were significantly downregulated in tumors, with a concomitant increase in the expression of IGF1R and key downstream effectors. Functional studies from miR-493 overexpression cells and nude-mouse models revealed the tumor suppressor functions of miR-493. Regulation studies revealed that Snail binds to the miR-493 promoter and represses it. We found the existence of a dynamic negative feedback loop in the regulation of IGF1R and miR-493 mediated via Snail. Our study showed that nicotine treatment significantly decreases the levels of miR-493-with a concomitant increase in the levels of Snail-an indication of progression of cells toward tumorigenesis, reestablishing the role of tobacco as a major risk factor for head and neck cancers and elucidating the mechanism behind nicotine-mediated tumorigenesis.
Collapse
|
|
37
|
Xu FP, Liu YH, Luo XL, Zhang F, Zhou HY, Ge Y, Liu C, Chen J, Luo DL, Yan LX, Mei P, Xu J, Zhuang HG. Overexpression of SRC-3 promotes esophageal squamous cell carcinoma aggressiveness by enhancing cell growth and invasiveness. Cancer Med 2016; 5:3500-3511. [PMID: 27781415 PMCID: PMC5224859 DOI: 10.1002/cam4.884] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2016] [Revised: 08/02/2016] [Accepted: 08/04/2016] [Indexed: 02/06/2023] Open
Abstract
Steroid receptor coactivator‐3 (SRC‐3), a transcriptional coactivator for nuclear receptors and other transcription factors, plays an important role in the genesis and progression of several cancers. However, studies investigated the role of SRC‐3 in esophageal squamous cell carcinomas (ESCCs) are limited, and the role of SRC‐3 in tumor progression remains unclear. We examined the expression of SRC‐3 in 8 ESCC cell lines and 302 human ESCC tissues by qPCR, Western blot, and immunohistochemistry. In addition, ESCC cell lines were subjected to proliferation and invasion assays, tumorigenicity assay, flow cytometry assay, qPCR, Western blot, and Chromatin Immunoprecipitation assay to investigate the role of SRC‐3 in cancer progression. SRC‐3 was overexpressed in 48% of cases and correlated with poor overall (P = 0.0076) and progression‐free (P = 0.0069) survival of surgically resected ESCC patient. Cox regression analysis revealed that SRC‐3 is an independent prognostic marker. Furthermore, we found that activation of insulin‐like growth factor (IGF)/AKT) was involved in the SRC‐3 on the cell growth and invasiveness in two ESCC cell lines, Eca109 and EC18 cells. SRC‐3 overexpression is clinically and functionally relevant to the progression of human ESCC, and might be a useful molecular target for ESCC prognosis and treatment.
Collapse
Affiliation(s)
- Fang-Ping Xu
- Department of Pathology and Laboratory Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yan-Hui Liu
- Department of Pathology and Laboratory Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xin-Lan Luo
- Department of Pathology and Laboratory Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Fen Zhang
- Department of Pathology and Laboratory Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Hai-Yu Zhou
- Department of Thoracic Surgery, Cancer Center, Guangdong General Hospital, Guangzhou, China
| | - Yan Ge
- Department of Pathology and Laboratory Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Chao Liu
- Department of Pathology and Laboratory Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Jie Chen
- Department of Pathology and Laboratory Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Dong-Lan Luo
- Department of Pathology and Laboratory Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Li-Xu Yan
- Department of Pathology and Laboratory Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Ping Mei
- Department of Pathology and Laboratory Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Jie Xu
- Department of Pathology and Laboratory Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Heng-Guo Zhuang
- Department of Pathology and Laboratory Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
| |
Collapse
|
|
38
|
Liu YA, Gregor VE. A Practical and Scalable Synthesis of GTx-134, an IGF-1R Inhibitor. J Heterocycl Chem 2016. [DOI: 10.1002/jhet.2443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Yahu A. Liu
- ChemBridge Research Laboratories, Inc.; San Diego California 92127 USA
| | - Vlad E. Gregor
- ChemBridge Research Laboratories, Inc.; San Diego California 92127 USA
| |
Collapse
|
|
39
|
Matsumoto F, Ohba S, Fujimaki M, Ikeda K. The value of insulin-like growth factor-1 receptor for predicting early glottic carcinoma response to radiotherapy. Auris Nasus Larynx 2016; 43:440-5. [DOI: 10.1016/j.anl.2015.11.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 11/09/2015] [Accepted: 11/16/2015] [Indexed: 12/19/2022]
|
|
40
|
Grant WB. Using Multicountry Ecological and Observational Studies to Determine Dietary Risk Factors for Alzheimer's Disease. J Am Coll Nutr 2016; 35:476-89. [DOI: 10.1080/07315724.2016.1161566] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
|
|
41
|
Ribezzo F, Shiloh Y, Schumacher B. Systemic DNA damage responses in aging and diseases. Semin Cancer Biol 2016; 37-38:26-35. [PMID: 26773346 PMCID: PMC4886830 DOI: 10.1016/j.semcancer.2015.12.005] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 12/28/2015] [Accepted: 12/31/2015] [Indexed: 01/09/2023]
Abstract
The genome is constantly attacked by a variety of genotoxic insults. The causal role for DNA damage in aging and cancer is exemplified by genetic defects in DNA repair that underlie a broad spectrum of acute and chronic human disorders that are characterized by developmental abnormalities, premature aging, and cancer predisposition. The disease symptoms are typically tissue-specific with uncertain genotype-phenotype correlation. The cellular DNA damage response (DDR) has been extensively investigated ever since yeast geneticists discovered DNA damage checkpoint mechanisms, several decades ago. In recent years, it has become apparent that not only cell-autonomous but also systemic DNA damage responses determine the outcome of genome instability in organisms. Understanding the mechanisms of non-cell-autonomous DNA damage responses will provide important new insights into the role of genome instability in human aging and a host of diseases including cancer and might better explain the complex phenotypes caused by genome instability.
Collapse
Affiliation(s)
- Flavia Ribezzo
- Institute for Genome Stability in Ageing and Disease, Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD) Research Center, Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Yosef Shiloh
- The David and Inez Myers Laboratory for Genetic Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Björn Schumacher
- Institute for Genome Stability in Ageing and Disease, Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD) Research Center, Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
| |
Collapse
|
|
42
|
Girnita L, Takahashi SI, Crudden C, Fukushima T, Worrall C, Furuta H, Yoshihara H, Hakuno F, Girnita A. Chapter Seven - When Phosphorylation Encounters Ubiquitination: A Balanced Perspective on IGF-1R Signaling. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 141:277-311. [PMID: 27378760 DOI: 10.1016/bs.pmbts.2016.04.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Cell-surface receptors govern the critical information passage from outside to inside the cell and hence control important cellular decisions such as survival, growth, and differentiation. These receptors, structurally grouped into different families, utilize common intracellular signaling-proteins and pathways, yet promote divergent biological consequences. In rapid processing of extracellular signals to biological outcomes, posttranslational modifications offer a repertoire of protein processing options. Protein ubiquitination was originally identified as a signal for protein degradation through the proteasome system. It is now becoming increasingly recognized that both ubiquitin and ubiquitin-like proteins, all evolved from a common ubiquitin structural superfold, are used extensively by the cell and encompass signal tags for many different cellular fates. In this chapter we examine the current understanding of the ubiquitin regulation surrounding the insulin-like growth factor and insulin signaling systems, major members of the larger family of receptor tyrosine kinases (RTKs) and key regulators of fundamental physiological and pathological states.
Collapse
Affiliation(s)
- L Girnita
- Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
| | - S-I Takahashi
- Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - C Crudden
- Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - T Fukushima
- Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan; Department of Biological Sciences, Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, Kanagawa, Japan
| | - C Worrall
- Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - H Furuta
- Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - H Yoshihara
- Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - F Hakuno
- Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - A Girnita
- Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Dermatology Department, Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
43
|
Huang S, Peter Rodemann H, Harari PM. Molecular Targeting of Growth Factor Receptor Signaling in Radiation Oncology. Recent Results Cancer Res 2016; 198:45-87. [PMID: 27318681 DOI: 10.1007/978-3-662-49651-0_3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Ionizing radiation has been shown to activate and interact with multiple growth factor receptor pathways that can influence tumor response to therapy. Among these receptor interactions, the epidermal growth factor receptor (EGFR) has been the most extensively studied with mature clinical applications during the last decade. The combination of radiation and EGFR-targeting agents using either monoclonal antibody (mAb) or small-molecule tyrosine kinase inhibitor (TKI) offers a promising approach to improve tumor control compared to radiation alone. Several underlying mechanisms have been identified that contribute to improved anti-tumor capacity after combined treatment. These include effects on cell cycle distribution, apoptosis, tumor cell repopulation, DNA damage/repair, and impact on tumor vasculature. However, as with virtually all cancer drugs, patients who initially respond to EGFR-targeted agents may eventually develop resistance and manifest cancer progression. Several potential mechanisms of resistance have been identified including mutations in EGFR and downstream signaling molecules, and activation of alternative member-bound tyrosine kinase receptors that bypass the inhibition of EGFR signaling. Several strategies to overcome the resistance are currently being explored in preclinical and clinical models, including agents that target the EGFR T790 M resistance mutation or target multiple EGFR family members, as well as agents that target other receptor tyrosine kinase and downstream signaling sites. In this chapter, we focus primarily on the interaction of radiation with anti-EGFR therapies to summarize this promising approach and highlight newly developing opportunities.
Collapse
Affiliation(s)
- Shyhmin Huang
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue K4/336 CSC, Madison, WI, 53792, USA
- Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, WIMR 3136, 1111 Highland Ave Madison, Madison, WI, 53705, USA
| | - H Peter Rodemann
- Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tübingen, Röntgenweg, 72076, Tübingen, Germany
| | - Paul M Harari
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue K4/336 CSC, Madison, WI, 53792, USA.
| |
Collapse
|
|
44
|
Feitelson MA, Arzumanyan A, Kulathinal RJ, Blain SW, Holcombe RF, Mahajna J, Marino M, Martinez-Chantar ML, Nawroth R, Sanchez-Garcia I, Sharma D, Saxena NK, Singh N, Vlachostergios PJ, Guo S, Honoki K, Fujii H, Georgakilas AG, Bilsland A, Amedei A, Niccolai E, Amin A, Ashraf SS, Boosani CS, Guha G, Ciriolo MR, Aquilano K, Chen S, Mohammed SI, Azmi AS, Bhakta D, Halicka D, Keith WN, Nowsheen S. Sustained proliferation in cancer: Mechanisms and novel therapeutic targets. Semin Cancer Biol 2015; 35 Suppl:S25-S54. [PMID: 25892662 PMCID: PMC4898971 DOI: 10.1016/j.semcancer.2015.02.006] [Citation(s) in RCA: 456] [Impact Index Per Article: 45.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 02/20/2015] [Accepted: 02/23/2015] [Indexed: 02/08/2023]
Abstract
Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression.
Collapse
Affiliation(s)
- Mark A Feitelson
- Department of Biology, Temple University, Philadelphia, PA, United States.
| | - Alla Arzumanyan
- Department of Biology, Temple University, Philadelphia, PA, United States
| | - Rob J Kulathinal
- Department of Biology, Temple University, Philadelphia, PA, United States
| | - Stacy W Blain
- Department of Pediatrics, State University of New York, Downstate Medical Center, Brooklyn, NY, United States
| | - Randall F Holcombe
- Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, United States
| | - Jamal Mahajna
- MIGAL-Galilee Technology Center, Cancer Drug Discovery Program, Kiryat Shmona, Israel
| | - Maria Marino
- Department of Science, University Roma Tre, V.le G. Marconi, 446, 00146 Rome, Italy
| | - Maria L Martinez-Chantar
- Metabolomic Unit, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Technology Park of Bizkaia, Bizkaia, Spain
| | - Roman Nawroth
- Department of Urology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Isidro Sanchez-Garcia
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca, Spain
| | - Dipali Sharma
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Neeraj K Saxena
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, United States
| | - Neetu Singh
- Tissue and Cell Culture Unit, CSIR-Central Drug Research Institute, Council of Scientific & Industrial Research, Lucknow, India
| | | | - Shanchun Guo
- Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Kanya Honoki
- Department of Orthopedic Surgery, Nara Medical University, Kashihara 634-8521, Japan
| | - Hiromasa Fujii
- Department of Orthopedic Surgery, Nara Medical University, Kashihara 634-8521, Japan
| | - Alexandros G Georgakilas
- Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens, Zografou 15780, Athens, Greece
| | - Alan Bilsland
- Institute of Cancer Sciences, University of Glasgow, UK
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Elena Niccolai
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Amr Amin
- Department of Biology, College of Science, UAE University, Al-Ain, United Arab Emirates
| | - S Salman Ashraf
- Department of Chemistry, College of Science, UAE University, Al-Ain, United Arab Emirates
| | - Chandra S Boosani
- Department of BioMedical Sciences, Creighton University, Omaha, NE, United States
| | - Gunjan Guha
- School of Chemical and Bio Technology, SASTRA University, Thanjavur, India
| | - Maria Rosa Ciriolo
- Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Katia Aquilano
- Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Sophie Chen
- Department of Research and Development, Ovarian and Prostate Cancer Research Trust Laboratory, Guildford, Surrey GU2 7YG, United Kingdom
| | - Sulma I Mohammed
- Department of Comparative Pathobiology, Purdue University Center for Cancer Research, West Lafayette, IN, United States
| | - Asfar S Azmi
- Department of Pathology, Karmonas Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States
| | - Dipita Bhakta
- School of Chemical and Bio Technology, SASTRA University, Thanjavur, India
| | - Dorota Halicka
- Brander Cancer Research Institute, Department of Pathology, New York Medical College, Valhalla, NY, United States
| | - W Nicol Keith
- Institute of Cancer Sciences, University of Glasgow, UK
| | - Somaira Nowsheen
- Mayo Graduate School, Mayo Medical School, Mayo Clinic Medical Scientist Training Program, Rochester, MN, United States
| |
Collapse
|
|
45
|
Curcumol Inhibits Growth and Induces Apoptosis of Colorectal Cancer LoVo Cell Line via IGF-1R and p38 MAPK Pathway. Int J Mol Sci 2015; 16:19851-67. [PMID: 26307972 PMCID: PMC4581329 DOI: 10.3390/ijms160819851] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 07/27/2015] [Accepted: 07/30/2015] [Indexed: 01/07/2023] Open
Abstract
Curcumol, isolated from the traditional medical plant Rhizoma Curcumae, is the bioactive component of Zedoary oil, whose potential anti-tumor effect has attracted considerable attention in recent years. Though many researchers have reported curcumol and its bioactivity, the potential molecular mechanism for its anti-cancer effect in colorectal cancer LoVo cells still remains unclear. In the present study, we found that curcumol showed growth inhibition and induced apoptosis of LoVo cells in a dose- and time-dependent manner. The occurrence of its proliferation inhibition and apoptosis came with suppression of IGF-1R expression, and then increased the phosphorylation of p38 mitogen activated protein kinase (MAPK), which might result in a cascade response by inhibiting the CREB survival pathway and finally triggered Bax/Bcl-2 and poly(ADP-ribose) polymerase 1 (PARP-1) apoptosis signals. Moreover, curcumol inhibited colorectal cancer in xenograft models of nude mice. Immunohistochemical and Western blot analysis revealed that curcumol could decrease the expression of ki-67, Bcl-2 as well as CREB1, and increase the expression of Bax and the phosphorylation of p38, which were consistent with our in vitro study. Overall, our in vitro and in vivo data confirmed the anti-cancer activity of curcumol, which was related to a significant inhibition of IGF-1R and activation of p38 MAPKs, indicating that curcumol may be a potential anti-tumor agent for colorectal carcinoma therapy.
Collapse
|
|
46
|
Gately K, Forde L, Gray S, Morris D, Corvin A, Tewari P, O'Byrne K. Mutational analysis of the insulin-like growth factor 1 receptor tyrosine kinase domain in non-small cell lung cancer patients. Mol Clin Oncol 2015; 3:1073-1079. [PMID: 26623053 DOI: 10.3892/mco.2015.580] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 04/02/2015] [Indexed: 11/06/2022] Open
Abstract
The insulin-like growth factor 1 receptor (IGF1R) pathway plays an important role in the pathogenesis of non-small cell lung cancer (NSCLC) and also provides a mechanism of resistance to targeted therapies. IGF1R is therefore an ideal therapeutic target and several inhibitors have entered clinical trials. However, thus far the response to these inhibitors has been poor, highlighting the importance of predictive biomarkers to identify patient cohorts who will benefit from these targeted agents. It is well-documented that mutations and/or deletions in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain predict sensitivity of NSCLC patients to EGFR TK inhibitors. Single-nucleotide polymorphisms (SNPs) in the IGF pathway have been associated with disease, including breast and prostate cancer. The aim of the present study was to elucidate whether the IGF1R TK domain harbours SNPs, somatic mutations or deletions in NSCLC patients and correlates the mutation status to patient clinicopathological data and prognosis. Initially 100 NSCLC patients were screened for mutations/deletions in the IGF1R TK domain (exons 16-21) by sequencing analysis. Following the identification of SNP rs2229765, a further 98 NSCLC patients and 866 healthy disease-free control patients were genotyped using an SNP assay. The synonymous SNP (rs2229765) was the only aberrant base change identified in the IGF1R TK domain of 100 NSCLC patients initially analysed. SNP rs2229765 was detected in exon 16 and was found to have no significant association between IGF1R expression and survival. The GA genotype was identified in 53.5 and 49.4% of NSCLC patients and control individuals, respectively. No significant difference was found in the genotype (P=0.5487) or allele (P=0.9082) frequencies between the case and control group. The present findings indicate that in contrast to the EGFR TK domain, the IGF1R TK domain is not frequently mutated in NSCLC patients. The synonymous SNP (rs2229765) had no significant association between IGF1R expression and survival in the cohort of NSCLC patients.
Collapse
Affiliation(s)
- Kathy Gately
- Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Republic of Ireland
| | - Lydia Forde
- Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Republic of Ireland
| | - Stephen Gray
- Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Republic of Ireland
| | - Derek Morris
- Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Republic of Ireland
| | - Aidan Corvin
- Discipline of Biochemistry, National University of Ireland, Galway, Republic of Ireland
| | - Prerna Tewari
- Molecular Pathology Research Group, Trinity College, Coombe Womens and Infants University Hospital, Dublin, Republic of Ireland
| | - Kenneth O'Byrne
- Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Republic of Ireland ; Medical Oncology, Princess Alexandra Hospital, Queensland University of Technology, Translational Research Institute, Brisbane, Queensland, Australia
| |
Collapse
|
|
47
|
Xu W, Hang M, Yuan CY, Wu FL, Chen SB, Xue K. MicroRNA-139-5p inhibits cell proliferation and invasion by targeting insulin-like growth factor 1 receptor in human non-small cell lung cancer. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:3864-3870. [PMID: 26097570 PMCID: PMC4466957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 03/23/2015] [Indexed: 06/04/2023]
Abstract
INTRODUCTION Increasing evidence suggested that microRNAs (miRNAs) play a critical role in tumorigenesis. Decreased expression of miRNA-139-5p has been observed in various types of cancers. However, the biological function of miRNA-139-5p in non-small cell lung cancer (NSCLC) is still largely unknown. METHODS Quantitative real-time PCR (qRT-PCR) was used to explore the expression level of miRNA-139-5p in NSCLC tissues and cell lines. Then, we investigated the role of miRNA-139-5p to determine its potential roles on lung cancer cell proliferation, migration and invasion in vitro. A luciferase reporter assay was performed to confirm the target gene of miRNA-139-5p and the results were validated in renal cancer cells. RESULTS miRNA-139-5p was significantly decreased in NSCLC tissues and cell lines. Over-expression of miRNA-139-5p could inhibit lung cancer cell proliferation, migration, and invasion in vitro. Furthermore, we identified insulin-like growth factor 1 receptor (IGF1R) as a target of miR-139-5p and miR-139-5p function as a tumor suppressor via targeting IGF1R in NSCLC. CONCLUSIONS Our results indicated that miR-139-5p acts as a tumor suppressor in NSCLC partially via down-regulating IGF1R expression.
Collapse
Affiliation(s)
- Wei Xu
- Medical Oncology, Nanjing Medical University Affiliated Wuxi Second HospitalWuxi 214002, China
| | - Meng Hang
- Medical Oncology, Nanjing Medical University Affiliated Wuxi Second HospitalWuxi 214002, China
| | - Chen-Ye Yuan
- Medical Oncology, Nanjing Medical University Affiliated Wuxi Second HospitalWuxi 214002, China
| | - Fu-Lin Wu
- Medical Oncology, Nanjing Medical University Affiliated Wuxi Second HospitalWuxi 214002, China
| | - Shu-Bo Chen
- Medical Oncology, Nanjing Medical University Affiliated Wuxi Second HospitalWuxi 214002, China
| | - Kai Xue
- Medical Oncology, Fudan University Shanghai Cancer CenterShanghai 200032, China
| |
Collapse
|
|
48
|
MATYSZEWSKI ARTUR, CZARNECKA ANNAM, SOLAREK WOJCIECH, KORZEŃ PIOTR, SAFIR ILANJ, KUKWA WOJCIECH, SZCZYLIK CEZARY. Molecular basis of carcinogenesis in diabetic patients (Review). Int J Oncol 2015; 46:1435-43. [DOI: 10.3892/ijo.2015.2865] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 12/10/2014] [Indexed: 11/05/2022] Open
|
|
49
|
Papadatos-Pastos D, De Miguel Luken MJ, Yap TA. Combining targeted therapeutics in the era of precision medicine. Br J Cancer 2015; 112:1-3. [PMID: 25562565 PMCID: PMC4453608 DOI: 10.1038/bjc.2014.558] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- D Papadatos-Pastos
- Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey, UK
- Drug Development Unit, Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
| | - M J De Miguel Luken
- Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey, UK
- Drug Development Unit, Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
| | - Timothy A Yap
- Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey, UK
- Drug Development Unit, Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
| |
Collapse
|
|
50
|
Zhang J, Huang FF, Wu DS, Li WJ, Zhan HE, Peng MY, Fang P, Cao PF, Zhang MM, Zeng H, Chen FP. SUMOylation of insulin-like growth factor 1 receptor, promotes proliferation in acute myeloid leukemia. Cancer Lett 2014; 357:297-306. [PMID: 25448401 DOI: 10.1016/j.canlet.2014.11.052] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 11/18/2014] [Accepted: 11/18/2014] [Indexed: 10/24/2022]
Abstract
Current valid treatments for acute myeloid leukemia (AML) include chemotherapy and hematopoietic stem cell transplantation, which are defective and limited respectively. The insulin-like growth factor 1 receptor (IGF-1R) is up-regulated in many solid tumors; therefore, it may be a target for tumor therapy. Interestingly, IGF-1R is modified by SUMOylation, a type of reversible post-translational modification. In this study, we found that IGF-1R was increased in both cell lines and clinical samples of AML and was modified by SUMO-1. Furthermore, IGF-1, ligand of IGF-1R, induced the up-regulation of IGF-1R and increased the proliferation of leukemia cell line. After mutation of Lys(1025) and Lys(1100) in IGF-1R, the evolutionarily conserved lysine residues were identified as the SUMOylation sites of IGF-1R, because the SUMOylation of IGF-1R in these mutants was significantly inhibited. Furthermore, the cell proliferation mediated by IGF-1 was also reduced. After inhibition of UBC9, the activating enzyme of SUMOylation, co-expression of IGF-1R and SUMO-1 was down-regulated, and cell proliferation was also inhibited. However, cell apoptosis was not significantly affected. These results suggest that IGF-1R and its SUMOylation may be a new therapeutic target for strategy of AML.
Collapse
Affiliation(s)
- Jian Zhang
- Department of Hematology, Xiang-Ya Hospital, Central South University, 87 Xiang-Ya Road, Changsha 410008, China
| | - Fang-Fang Huang
- Department of Hematology, Zhong-Shan Hospital, Xiamen University, Xiamen, China
| | - Deng-Shu Wu
- Department of Hematology, Xiang-Ya Hospital, Central South University, 87 Xiang-Ya Road, Changsha 410008, China
| | - Wen-Jin Li
- Department of Hematology, Xiang-Ya Hospital, Central South University, 87 Xiang-Ya Road, Changsha 410008, China
| | - Hui-En Zhan
- Department of Hematology, Xiang-Ya Hospital, Central South University, 87 Xiang-Ya Road, Changsha 410008, China
| | - Min-Yuan Peng
- Department of Hematology, Xiang-Ya Hospital, Central South University, 87 Xiang-Ya Road, Changsha 410008, China
| | - Peng Fang
- Department of Hematology, Xiang-Ya Hospital, Central South University, 87 Xiang-Ya Road, Changsha 410008, China
| | - Peng-Fei Cao
- Department of Hematology, Xiang-Ya Hospital, Central South University, 87 Xiang-Ya Road, Changsha 410008, China
| | - Meng-Meng Zhang
- Department of Hematology, Xiang-Ya Hospital, Central South University, 87 Xiang-Ya Road, Changsha 410008, China
| | - Hui Zeng
- Department of Hematology, Xiang-Ya Hospital, Central South University, 87 Xiang-Ya Road, Changsha 410008, China.
| | - Fang-Ping Chen
- Department of Hematology, Xiang-Ya Hospital, Central South University, 87 Xiang-Ya Road, Changsha 410008, China.
| |
Collapse
|