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1
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Galal MA, Al-Rimawi M, Hajeer A, Dahman H, Alouch S, Aljada A. Metformin: A Dual-Role Player in Cancer Treatment and Prevention. Int J Mol Sci 2024; 25:4083. [PMID: 38612893 PMCID: PMC11012626 DOI: 10.3390/ijms25074083] [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: 03/06/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer continues to pose a significant global health challenge, as evidenced by the increasing incidence rates and high mortality rates, despite the advancements made in chemotherapy. The emergence of chemoresistance further complicates the effectiveness of treatment. However, there is growing interest in the potential of metformin, a commonly prescribed drug for type 2 diabetes mellitus (T2DM), as an adjuvant chemotherapy agent in cancer treatment. Although the precise mechanism of action of metformin in cancer therapy is not fully understood, it has been found to have pleiotropic effects, including the modulation of metabolic pathways, reduction in inflammation, and the regulation of cellular proliferation. This comprehensive review examines the anticancer properties of metformin, drawing insights from various studies conducted in vitro and in vivo, as well as from clinical trials and observational research. This review discusses the mechanisms of action involving both insulin-dependent and independent pathways, shedding light on the potential of metformin as a therapeutic agent for different types of cancer. Despite promising findings, there are challenges that need to be addressed, such as conflicting outcomes in clinical trials, considerations regarding dosing, and the development of resistance. These challenges highlight the importance of further research to fully harness the therapeutic potential of metformin in cancer treatment. The aims of this review are to provide a contemporary understanding of the role of metformin in cancer therapy and identify areas for future exploration in the pursuit of effective anticancer strategies.
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Affiliation(s)
- Mariam Ahmed Galal
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK
| | - Mohammed Al-Rimawi
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | | | - Huda Dahman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Samhar Alouch
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
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2
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Wang NF, Jue TR, Holst J, Gunter JH. Systematic review of antitumour efficacy and mechanism of metformin activity in prostate cancer models. BJUI COMPASS 2023; 4:44-58. [PMID: 36569495 PMCID: PMC9766874 DOI: 10.1002/bco2.187] [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: 06/08/2022] [Revised: 07/07/2022] [Accepted: 08/08/2022] [Indexed: 12/27/2022] Open
Abstract
Metformin, the first line pharmacotherapy for type 2 diabetes has demonstrated favourable effects in prostate cancer (PCa) across a range of studies evaluating PCa patient outcomes amongst metformin users. However, a lack of rigorously conducted prospective studies has stalled clinical use in this setting. Despite multiple studies evaluating the mechanisms underpinning antitumour effects of metformin in PCa, to date, no reviews have compared these findings. This systematic review and meta-analysis consolidates the mechanisms accounting for the antitumour effect of metformin in PCa and evaluates the antitumour efficacy of metformin in preclinical PCa studies. Data were obtained through Medline and EMBASE, extracted by two independent assessors. Risk of bias was assessed using the TOXR tool. Meta-analysis compared in vivo reductions of PCa tumour volume with metformin. In total, 447 articles were identified with 80 duplicates, and 261 articles excluded based on eligibility criteria. The remaining 106 articles were assessed and 71 excluded, with 35 articles included for systematic review, and eight included for meta-analysis. The mechanisms of action of metformin regarding tumour growth, viability, migration, invasion, cell metabolism, and activation of signalling cascades are individually discussed. The mechanisms by which metformin inhibits PCa cell growth are multimodal. Metformin regulates expression of multiple proteins/genes to inhibit cellular proliferation, cell cycle progression, and cellular invasion and migration. Published in vivo studies also conclusively demonstrate that metformin inhibits PCa growth. This highlights the potential of metformin to be repurposed as an anticancer agent, warranting further investigation of metformin in the setting of PCa.
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Affiliation(s)
- Nan Fang Wang
- School of Medical SciencesUNSW SydneySydneyNSWAustralia
- Prince of Wales Clinical SchoolUNSW SydneySydneyNSWAustralia
| | - Toni Rose Jue
- Prince of Wales Clinical SchoolUNSW SydneySydneyNSWAustralia
| | - Jeff Holst
- School of Medical SciencesUNSW SydneySydneyNSWAustralia
- Prince of Wales Clinical SchoolUNSW SydneySydneyNSWAustralia
| | - Jennifer H. Gunter
- Australian Prostate Cancer Research Centre‐Queensland, Centre for Genomic and Personalised Health, School of Biomedical Sciences, Faculty of Health, Translational Research InstituteQueensland University of Technology (QUT)BrisbaneQLDAustralia
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3
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Sanati M, Aminyavari S, Mollazadeh H, Motamed-Sanaye A, Bibak B, Mohtashami E, Teng Y, Afshari AR, Sahebkar A. The Potential Therapeutic Impact of Metformin in Glioblastoma Multiforme. Curr Med Chem 2023; 30:857-877. [PMID: 35796457 DOI: 10.2174/0929867329666220707103525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 03/13/2022] [Accepted: 04/16/2022] [Indexed: 02/08/2023]
Abstract
In terms of frequency and aggressiveness, glioblastoma multiforme (GBM) is undoubtedly the most frequent and fatal primary brain tumor. Despite advances in clinical management, the response to current treatments is dismal, with a 2-year survival rate varying between 6 and 12 percent. Metformin, a derivative of biguanide widely used in treating type 2 diabetes, has been shown to extend the lifespan of patients with various malignancies. There is limited evidence available on the long-term survival of GBM patients who have taken metformin. This research examined the literature to assess the connection between metformin's anticancer properties and GBM development. Clinical findings, together with the preclinical data from animal models and cell lines, are included in the present review. This comprehensive review covers not only the association of hyperactivation of the AMPK pathway with the anticancer activity of metformin but also other mechanisms underpinning its role in apoptosis, cell proliferation, metastasis, as well as its chemo-radio-sensitizing behavior against GBM. Current challenges and future directions for developments and applications of metformin-based therapeutics are also discussed.
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Affiliation(s)
- Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Samaneh Aminyavari
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Mollazadeh
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Ali Motamed-Sanaye
- Student Research Committee, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Bahram Bibak
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Elmira Mohtashami
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yong Teng
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA30322, USA
| | - Amir R Afshari
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Medicine, The University of Western Australia, Perth, Australia
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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4
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Olokpa E, Mandape SN, Pratap S, Stewart LMV. Metformin regulates multiple signaling pathways within castration-resistant human prostate cancer cells. BMC Cancer 2022; 22:1025. [PMID: 36175875 PMCID: PMC9520831 DOI: 10.1186/s12885-022-10115-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 09/19/2022] [Indexed: 11/25/2022] Open
Abstract
Background The biguanide metformin has been shown to not only reduce circulating glucose levels but also suppress in vitro and in vivo growth of prostate cancer. However, the mechanisms underlying the anti-tumor effects of metformin in advanced prostate cancers are not fully understood. The goal of the present study was to define the signaling pathways regulated by metformin in androgen-receptor (AR) positive, castration-resistant prostate cancers. Methods Our group used RNA sequencing (RNA-seq) to examine genes regulated by metformin within the C4–2 human prostate cancer cell line. Western blot analysis and quantitative RT-PCR were used to confirm alterations in gene expression and further explore regulation of protein expression by metformin. Results Data from the RNA-seq analysis revealed that metformin alters the expression of genes products involved in metabolic pathways, the spliceosome, RNA transport, and protein processing within the endoplasmic reticulum. Gene products involved in ErbB, insulin, mTOR, TGF-β, MAPK, and Wnt signaling pathways are also regulated by metformin. A subset of metformin-regulated gene products were genes known to be direct transcriptional targets of p53 or AR. Western blot analyses and quantitative RT-PCR indicated these alterations in gene expression are due in part to metformin-induced reductions in AR mRNA and protein levels. Conclusions Together, our results suggest metformin regulates multiple pathways linked to tumor growth and progression within advanced prostate cancer cells. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10115-3.
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Affiliation(s)
- Emuejevoke Olokpa
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Blvd., Nashville, TN, 37208, USA
| | - Sammed N Mandape
- School of Graduate Studies and Research, Bioinformatics Core, Meharry Medical College, 1005 Dr. D, B. Todd Jr. Blvd., Nashville, TN, 37208, USA
| | - Siddharth Pratap
- School of Graduate Studies and Research, Bioinformatics Core, Meharry Medical College, 1005 Dr. D, B. Todd Jr. Blvd., Nashville, TN, 37208, USA
| | - La Monica V Stewart
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Blvd., Nashville, TN, 37208, USA.
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5
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Birzniece V, Lam T, McLean M, Reddy N, Shahidipour H, Hayden A, Gurney H, Stone G, Hjortebjerg R, Frystyk J. Insulin-like growth factor role in determining the anti-cancer effect of metformin: RCT in prostate cancer patients. Endocr Connect 2022; 11:EC-21-0375. [PMID: 35324467 PMCID: PMC9066575 DOI: 10.1530/ec-21-0375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 03/23/2022] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Androgen deprivation therapy (ADT), a principal therapy in patients with prostate cancer, is associated with the development of obesity, insulin resistance, and hyperinsulinemia. Recent evidence indicates that metformin may slow cancer progression and improves survival in prostate cancer patients, but the mechanism is not well understood. Circulating insulin-like growth factors (IGFs) are bound to high-affinity binding proteins, which not only modulate the bioavailability and signalling of IGFs but also have independent actions on cell growth and survival. The aim of this study was to investigate whether metformin modulates IGFs, IGF-binding proteins (IGFBPs), and the pregnancy-associated plasma protein A (PAPP-A) - stanniocalcin 2 (STC2) axis. DESIGN AND METHODS In a blinded, randomised, cross-over design, 15 patients with prostate cancer on stable ADT received metformin and placebo treatment for 6 weeks each. Glucose metabolism along with circulating IGFs and IGFBPs was assessed. RESULTS Metformin significantly reduced the homeostasis model assessment as an index of insulin resistance (HOMA IR) and hepatic insulin resistance. Metformin also reduced circulating IGF-2 (P < 0.05) and IGFBP-3 (P < 0.01) but increased IGF bioactivity (P < 0.05). At baseline, IGF-2 correlated significantly with the hepatic insulin resistance (r2= 0.28, P < 0.05). PAPP-A remained unchanged but STC2 declined significantly (P < 0.05) following metformin administration. During metformin treatment, change in HOMA IR correlated with the change in STC2 (r2= 0.35, P < 0.05). CONCLUSION Metformin administration alters many components of the circulating IGF system, either directly or indirectly via improved insulin sensitivity. Reduction in IGF-2 and STC2 may provide a novel mechanism for a potential metformin-induced antineoplastic effect.
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Affiliation(s)
- Vita Birzniece
- School of Medicine, Western Sydney University, New South Wales, Australia
- Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia
- Garvan Institute of Medical Research, New South Wales, Australia
- School of Medical Sciences, University of New South Wales, New South Wales, Australia
- Correspondence should be addressed to V Birzniece:
| | - Teresa Lam
- School of Medicine, Western Sydney University, New South Wales, Australia
- Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia
- Department of Diabetes and Endocrinology, Westmead Hospital, New South Wales, Australia
| | - Mark McLean
- School of Medicine, Western Sydney University, New South Wales, Australia
- Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia
| | - Navneeta Reddy
- Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia
| | - Haleh Shahidipour
- School of Medicine, Western Sydney University, New South Wales, Australia
- Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia
| | - Amy Hayden
- School of Medicine, Western Sydney University, New South Wales, Australia
- Faculty of Medicine, Health and Human Sciences, Macquarie University, New South Wales, Australia
- Crown Princess Mary Cancer Centre, Westmead Hospital, New South Wales, Australia
| | - Howard Gurney
- Crown Princess Mary Cancer Centre, Westmead Hospital, New South Wales, Australia
| | - Glenn Stone
- School of Computing, Engineering and Mathematics, Western Sydney University, New South Wales, Australia
| | - Rikke Hjortebjerg
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Endocrine Research Unit, Department of Endocrinology, Odense University Hospital & Department of Clinical Research, Faculty of Health, University of Southern Denmark, Odense, Denmark
- Steno Diabetes Center Odense, Odense University Hospital & Department of Clinical Research, Faculty of Health, University of Southern Denmark, Odense, Denmark
| | - Jan Frystyk
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Endocrine Research Unit, Department of Endocrinology, Odense University Hospital & Department of Clinical Research, Faculty of Health, University of Southern Denmark, Odense, Denmark
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6
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Nalairndran G, Chung I, Abdul Razack AH, Chung FF, Hii L, Lim W, Looi CK, Mai C, Leong C. Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells. J Cell Mol Med 2021; 25:8187-8200. [PMID: 34322995 PMCID: PMC8419172 DOI: 10.1111/jcmm.16684] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 04/21/2021] [Accepted: 05/12/2021] [Indexed: 02/05/2023] Open
Abstract
Prostate cancer (PCa) is the second most common malignancy and is the fifth leading cause of cancer mortality among men globally. Docetaxel-based therapy remains the first-line treatment for metastatic castration-resistant prostate cancer. However, dose-limiting toxicity including neutropenia, myelosuppression and neurotoxicity is the major reason for docetaxel dose reductions and fewer cycles administered, despite a recent study showing a clear survival benefit with increased total number of docetaxel cycles in PCa patients. Although previous studies have attempted to improve the efficacy and reduce docetaxel toxicity through drug combination, no drug has yet demonstrated improved overall survival in clinical trial, highlighting the challenges of improving the activity of docetaxel monotherapy in PCa. Herein, we identified 15 lethality hits for which inhibition could enhance docetaxel sensitivity in PCa cells via a high-throughput kinome-wide loss-of-function screen. Further drug-gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA-approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel-induced apoptosis in PCa cells. Furthermore, inhibition of JAK1/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)-negative DU145 and PC3 cells, but not in the AR-positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2-specific inhibitor, fedratinib, suggesting that the synergistic effects are mainly mediated through JAK1 inhibition. In conclusion, the combination therapy with JAK1 inhibitors and docetaxel could be a useful therapeutic strategy in the treatment of prostate cancers.
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Affiliation(s)
- Geetha Nalairndran
- Department of PharmacologyFaculty of MedicineUniversity of MalayaKuala LumpurMalaysia
| | - Ivy Chung
- Department of PharmacologyFaculty of MedicineUniversity of MalayaKuala LumpurMalaysia
- University of Malaya Cancer Research InstituteFaculty of MedicineUniversity of MalayaKuala LumpurMalaysia
| | | | - Felicia Fei‐Lei Chung
- Mechanisms of Carcinogenesis Section (MCA)Epigenetics Group (EGE)International Agency for Research on Cancer World Health OrganizationLyon CEDEX 08France
| | - Ling‐Wei Hii
- Center for Cancer and Stem Cell ResearchInstitute for ResearchDevelopment and Innovation (IRDI)International Medical UniversityKuala LumpurMalaysia
- School of PharmacyInternational Medical UniversityKuala LumpurMalaysia
- School of Postgraduate StudiesInternational Medical UniversityKuala LumpurMalaysia
| | - Wei‐Meng Lim
- Center for Cancer and Stem Cell ResearchInstitute for ResearchDevelopment and Innovation (IRDI)International Medical UniversityKuala LumpurMalaysia
- School of PharmacyInternational Medical UniversityKuala LumpurMalaysia
| | - Chin King Looi
- Center for Cancer and Stem Cell ResearchInstitute for ResearchDevelopment and Innovation (IRDI)International Medical UniversityKuala LumpurMalaysia
- School of Postgraduate StudiesInternational Medical UniversityKuala LumpurMalaysia
| | - Chun‐Wai Mai
- Center for Cancer and Stem Cell ResearchInstitute for ResearchDevelopment and Innovation (IRDI)International Medical UniversityKuala LumpurMalaysia
- State Key Laboratory of Oncogenes and Related GenesRenji‐Med X Clinical Stem Cell Research CenterDepartment of UrologyRen Ji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Chee‐Onn Leong
- Center for Cancer and Stem Cell ResearchInstitute for ResearchDevelopment and Innovation (IRDI)International Medical UniversityKuala LumpurMalaysia
- School of PharmacyInternational Medical UniversityKuala LumpurMalaysia
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7
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Ibrahim S, Lowe JR, Bramante CT, Shah S, Klatt NR, Sherwood N, Aronne L, Puskarich M, Tamariz L, Palacio A, Bomberg E, Usher M, King S, Benson B, Vojta D, Tignanelli C, Ingraham N. Metformin and Covid-19: Focused Review of Mechanisms and Current Literature Suggesting Benefit. Front Endocrinol (Lausanne) 2021; 12:587801. [PMID: 34367059 PMCID: PMC8342037 DOI: 10.3389/fendo.2021.587801] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 05/11/2021] [Indexed: 01/08/2023] Open
Abstract
Metformin is the first-line medication for type 2 diabetes, but it also has a long history of improved outcomes in infectious diseases, such as influenza, hepatitis C, and in-vitro assays of zika. In the current Covid-19 pandemic, which has rapidly spread throughout the world, 4 observational studies have been published showing reduced mortality among individuals with home metformin use. There are several potential overlapping mechanisms by which metformin may reduce mortality from Covid-19. Metformin's past anti-infectious benefits have been both against the infectious agent directly, as well as by improving the underlying health of the human host. It is unknown if the lower mortality suggested by observational studies in patients infected with Covid-19 who are on home metformin is due to direct activity against the virus itself, improved host substrate, or both.
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Affiliation(s)
- Sherehan Ibrahim
- Department of Medicine, Division of General Internal Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Jamie R. Lowe
- MPH Program, Dartmouth College, Hanover, NH, United States
| | - Carolyn T. Bramante
- Department of Medicine, Division of General Internal Medicine, University of Minnesota, Minneapolis, MN, United States
- *Correspondence: Carolyn T. Bramante,
| | - Surbhi Shah
- Department of Medicine, Division of Hematology, Oncology and Transplant, University of Minnesota, Minneapolis, MN, United States
| | - Nichole R. Klatt
- Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Nancy Sherwood
- Department of Epidemiology, University of Minnesota, Minneapolis, MN, United States
| | - Louis Aronne
- Division of Endocrinology, Cornell Weill College of Medicine, New York, NY, United States
| | - Michael Puskarich
- Department of Emergency Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Leonardo Tamariz
- Division of Cardiology and Miami VA Healthcare Administration, University of Miami, Miami, FL, United States
| | - Ana Palacio
- Division of Cardiology and Miami VA Healthcare Administration, University of Miami, Miami, FL, United States
| | - Eric Bomberg
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Minnesota, Minneapolis, MN, United States
| | - Michael Usher
- Department of Medicine, Division of General Internal Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Samantha King
- Department of Medicine, Division of General Internal Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Brad Benson
- Department of Medicine, Division of General Internal Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Deneen Vojta
- UnitedHealth Group, Research and Development, Plymouth, MN, United States
| | - Chris Tignanelli
- Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Nicholas Ingraham
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Minnesota, Minneapolis, MN, United States
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Testosterone-loaded GM1 micelles targeted to the intracellular androgen receptor for the specific induction of genomic androgen signaling. Int J Pharm 2020; 591:119985. [DOI: 10.1016/j.ijpharm.2020.119985] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 10/08/2020] [Accepted: 10/11/2020] [Indexed: 02/07/2023]
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9
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Soleymani Fard S, Yazdanbod M, Sotoudeh M, Bashash D, Mahmoodzadeh H, Saliminejad K, Mousavi SA, Ghaffari SH, Alimoghaddam K. Prognostic and Therapeutic Significance of Androgen Receptor in Patients with Gastric Cancer. Onco Targets Ther 2020; 13:9821-9837. [PMID: 33061460 PMCID: PMC7537849 DOI: 10.2147/ott.s265364] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 08/29/2020] [Indexed: 01/02/2023] Open
Abstract
Purpose The clinical studies carried out in the last few decades unequivocally introduced activated androgen receptor (AR) as a pathogenic feature of human malignancies which not only endows cancer cells with survival advantage, but also may be exploited for anticancer interventions. Patients and Methods In this study, we have investigated the expression profile of AR and EMT-related genes in fresh gastric cancer (GC), adjacent nontumor and normal gastric tissues, as well as the effect and molecular mechanisms of AR inhibition in GC cell lines. Results Amongst 60 GC patients, 66.7% overexpressed AR that was remarkably correlated with the overexpression of Snail, β-catenin, Twist1, and STAT3. AR overexpression was also remarkably associated with unfavorable outcome (HR=3.478, P=0.001); however, multivariate Cox regression analysis indicated that it was not an independent prognostic factor (HR=2.089, P=0.056). This study has investigated simultaneous assessment of AR and EMT-related genes expression and indicated that concurrent overexpression of AR and Snail is an independent unfavorable factor for GC overall survival after adjustment with other variables (HR=2.382, P=0.021). Interestingly, the inhibition of AR signaling by potent AR antagonist enzalutamide suppressed cell growth, migration and invasion of GC cells via regulation of apoptosis-, cell cycle-, and EMT-related gene expressions. Conclusion Our findings have clinical importance proposing AR as an important prognostic factor involved in GC progression and metastasis, and submit AR inhibition as an appealing therapeutic approach for GC patients, either as a single agent or in a combined-modal strategy.
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Affiliation(s)
- Shahrzad Soleymani Fard
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Masoud Sotoudeh
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Habibollah Mahmoodzadeh
- Department of Surgical Oncology, Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Kioomars Saliminejad
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Asadollah Mousavi
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kamran Alimoghaddam
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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10
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Vella V, Malaguarnera R, Nicolosi ML, Morrione A, Belfiore A. Insulin/IGF signaling and discoidin domain receptors: An emerging functional connection. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:118522. [PMID: 31394114 DOI: 10.1016/j.bbamcr.2019.118522] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 07/30/2019] [Accepted: 07/31/2019] [Indexed: 12/28/2022]
Abstract
The insulin/insulin-like growth factor system (IIGFs) plays a fundamental role in the regulation of prenatal and postnatal growth, metabolism and homeostasis. As a consequence, dysregulation of this axis is associated with growth disturbance, type 2 diabetes, chronic inflammation and tumor progression. A functional crosstalk between IIGFs and discoidin domain receptors (DDRs) has been recently discovered. DDRs are non-integrin collagen receptors that canonically undergo slow and long-lasting autophosphorylation after binding to fibrillar collagen. While both DDR1 and DDR2 functionally interact with IIGFs, the crosstalk with DDR1 is so far better characterized. Notably, the IIGFs-DDR1 crosstalk presents a feed-forward mechanism, which does not require collagen binding, thus identifying novel non-canonical action of DDR1. Further studies are needed to fully explore the role of this IIGFs-DDRs functional loop as potential target in the treatment of inflammatory and neoplastic disorders.
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Affiliation(s)
- Veronica Vella
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | | | - Maria Luisa Nicolosi
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Andrea Morrione
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Antonino Belfiore
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy.
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11
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Ranasinghe WK, Williams S, Ischia J, Wetherell D, Baldwin G, Shulkes A, Sengupta S, Bolton D, Patel O. Metformin may offer no protective effect in men undergoing external beam radiation therapy for prostate cancer. BJU Int 2019; 123 Suppl 5:36-42. [DOI: 10.1111/bju.14709] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Weranja K.B. Ranasinghe
- Department of Urology; Austin Health; Heidelberg Vic. Australia
- Department of Surgery; University of Melbourne; Heidelberg Vic. Australia
| | - Scott Williams
- Peter MacCallum Cancer Institute; Parkville Vic. Australia
| | - Joseph Ischia
- Department of Urology; Austin Health; Heidelberg Vic. Australia
- Department of Surgery; University of Melbourne; Heidelberg Vic. Australia
| | - David Wetherell
- Department of Urology; Austin Health; Heidelberg Vic. Australia
| | - Graham Baldwin
- Department of Surgery; University of Melbourne; Heidelberg Vic. Australia
| | - Arthur Shulkes
- Department of Surgery; University of Melbourne; Heidelberg Vic. Australia
| | - Shomik Sengupta
- Department of Urology; Austin Health; Heidelberg Vic. Australia
- Department of Surgery; University of Melbourne; Heidelberg Vic. Australia
- Department of Urology; Eastern Health; Box Hill Vic Australia
- Eastern Health Clinical School; Monash University; Box Hill Vic Australia
| | - Damien Bolton
- Department of Urology; Austin Health; Heidelberg Vic. Australia
- Department of Surgery; University of Melbourne; Heidelberg Vic. Australia
| | - Oneel Patel
- Department of Surgery; University of Melbourne; Heidelberg Vic. Australia
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12
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Lee H, Lee M, Hong SK. CRTC2 as a novel prognostic biomarker for worse pathologic outcomes and biochemical recurrence after radical prostatectomy in patients with prostate cancer. Investig Clin Urol 2019; 60:84-90. [PMID: 30838340 PMCID: PMC6397930 DOI: 10.4111/icu.2019.60.2.84] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 01/21/2019] [Indexed: 11/18/2022] Open
Abstract
Purpose To identify the association between tumor metabolism and prostate cancer (PCa), we investigated the relationship between expression of metabolism-related genes and clinicopathologic outcomes in patients with localized PCa. Materials and Methods We prospectively collected periprostatic adipose tissue from 40 PCa patients and extracted the RNA of each sample. After cDNA was synthesized from the extracted RNA, we analyzed the expression of 18 metabolism-related genes using real-time polymerase chain reaction. We divided the subjects according to the pathologic Gleason score (pGS) and compared the expression of each gene. Subsequently, the clinicopathologic outcomes were also compared according to the expression of each gene. Results When we compared the expression of 18 metabolism-related genes between the high (≥4+3) and low pGS groups (3+4), there were significant differences in the expression of six genes (SREBP, SCD, FASN, ACLY, ECHS, and CRTC2; p<0.05). Among them, the subjects with low expression for CRTC2 showed significantly worse pathologic outcomes in terms of high pGS (≥4+3) (p=0.020) and higher rates of seminal vesicle invasion (p=0.017). The low CRTC2 group also showed significantly inferior biochemical recurrence-free survival than the high CRTC2 group (p=0.048). Conclusions We found that high pGS patients showed significant differences in expression of several metabolism-related genes compared with low pGS patients. Among those genes, CRTC2 showed the strongest association with pathologic outcome, as well as postoperative survival.
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Affiliation(s)
- Hakmin Lee
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Minseung Lee
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sung Kyu Hong
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Urology, Seoul National University College of Medicine, Seoul, Korea
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13
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Tasoulas J, Rodon L, Kaye FJ, Montminy M, Amelio AL. Adaptive Transcriptional Responses by CRTC Coactivators in Cancer. Trends Cancer 2019; 5:111-127. [PMID: 30755304 DOI: 10.1016/j.trecan.2018.12.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 12/03/2018] [Accepted: 12/07/2018] [Indexed: 01/09/2023]
Abstract
Adaptive stress signaling networks directly influence tumor development and progression. These pathways mediate responses that allow cancer cells to cope with both tumor cell-intrinsic and cell-extrinsic insults and develop acquired resistance to therapeutic interventions. This is mediated in part by constant oncogenic rewiring at the transcriptional level by integration of extracellular cues that promote cell survival and malignant transformation. The cAMP-regulated transcriptional coactivators (CRTCs) are a newly discovered family of intracellular signaling integrators that serve as the conduit to the basic transcriptional machinery to regulate a host of adaptive response genes. Thus, somatic alterations that lead to CRTC activation are emerging as key driver events in the development and progression of many tumor subtypes.
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Affiliation(s)
- Jason Tasoulas
- Lineberger Comprehensive Cancer Center, UNC School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; These authors contributed equally
| | - Laura Rodon
- Peptide Biology Laboratories, Salk Institute, La Jolla, CA, USA; These authors contributed equally
| | - Frederic J Kaye
- Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA; UF Health Cancer Center, University of Florida, Gainesville, FL, USA
| | - Marc Montminy
- Peptide Biology Laboratories, Salk Institute, La Jolla, CA, USA
| | - Antonio L Amelio
- Department of Oral and Craniofacial Health Sciences, UNC School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, Cancer Cell Biology Program, UNC School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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14
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Yu H, Zhong X, Gao P, Shi J, Wu Z, Guo Z, Wang Z, Song Y. The Potential Effect of Metformin on Cancer: An Umbrella Review. Front Endocrinol (Lausanne) 2019; 10:617. [PMID: 31620081 PMCID: PMC6760464 DOI: 10.3389/fendo.2019.00617] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 08/27/2019] [Indexed: 12/19/2022] Open
Abstract
Background: Metformin has been reported to possess anti-cancer properties in addition to glucose-lowering activity and numerous systematic reviews and meta-analyses have studied the association between metformin use and cancer incidence or survival outcomes. We performed an umbrella review to assess the robustness of these associations to facilitate proper interpretation of these results to inform clinical and policy decisions. Methods: We searched PubMed and Embase systematic reviews and meta-analyses investigating the effect of metformin use on cancer incidence or survival outcomes published from inception to September 2, 2018. We estimated the summary effect size, the 95% CI, and the 95% prediction interval, heterogeneity, evidence of small-study effects, and evidence of excess significance bias. Results: We included 21 systematic reviews and meta-analyses covering 11 major anatomical sites and 33 associations. There was strong evidence for the association between metformin use and decreased pancreatic cancer incidence. The association between metformin use and improved colorectal cancer overall survival (OS) was supported by highly suggestive evidence. Seven associations (all cancer incidence, all cancer OS, breast cancer OS, colorectal cancer incidence, liver cancer incidence, lung cancer OS, and pancreatic cancer OS) presented only suggestive evidence. The remaining 24 associations were supported by weak or not-suggestive evidence. Conclusions: Associations between metformin use and pancreatic cancer incidence or colorectal cancer OS are supported by strong or highly suggestive evidence, respectively. However, these results should be interpreted with caution due to the poor methodological quality of the systematic reviews and meta-analyses.
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15
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Delma MI. Three May Be Better Than Two: A Proposal for Metformin Addition to PI3K/Akt Inhibitor-antiandrogen Combination in Castration-resistant Prostate Cancer. Cureus 2018; 10:e3403. [PMID: 30533337 PMCID: PMC6278999 DOI: 10.7759/cureus.3403] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Prostate cancer is a prevalent malignant disease. Castration-resistant prostate cancer (CRPC) is a poor prognosis form that develops upon resistance to first-line androgen deprivation therapy. Intensive research is ongoing to find efficient therapeutics for this refractory state. Actually, the combination of PI3K/Akt inhibitors with new-generation antiandrogens is among the most promising therapeutic schemes, although not yet at the optimal level. Metformin effects on prostate cancer, notably its therapeutic targets shared with antiandrogens and/or PI3K/Akt inhibitors, are reviewed in this article. From that, the hypothesis of PI3K/Akt-antiandrogens dual blockade optimization by metformin addition in CRPC will be deduced.
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16
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Faggi L, Giustina A, Tulipano G. Effects of metformin on cell growth and AMPK activity in pituitary adenoma cell cultures, focusing on the interaction with adenylyl cyclase activating signals. Mol Cell Endocrinol 2018; 470:60-74. [PMID: 28962892 DOI: 10.1016/j.mce.2017.09.030] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 09/21/2017] [Accepted: 09/25/2017] [Indexed: 01/27/2023]
Abstract
For a few years we have been investigating AMP-activated protein kinase (AMPK) as a target for drug therapy of GH-secreting pituitary adenomas. Aim of this study was to investigate the direct effects of metformin, which causes AMPK activation in different cell types, on rat pituitary adenoma cell growth and on related cell signalling pathways. Our results suggest that metformin can exert a growth-inhibitory activity in rat pituitary tumor cells mediated by AMPK activation, although multiple mechanisms are most likely involved. Membrane proteins, including growth factor receptors, are valuable targets of AMPK. The inhibition of the mTOR-p70S6 kinase signalling pathway plays a role in the suppressive effect of metformin on pituitary tumor cell growth. Metformin did not affect the MTT reduction activity in energetic stress conditions. Finally, metformin was still able to induce AMPK activation and to inhibit cell growth in cells treated with forskolin and in transfected cells overexpressing GHRH-receptor and treated with GHRH. Hence, adenylyl cyclase over-activation does not account for the lack of response of some human pituitary tumors to AMPK-activating compounds in vitro.
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Affiliation(s)
- Lara Faggi
- Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Italy
| | - Andrea Giustina
- Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Italy; Endocrine Service, University of Brescia, Italy
| | - Giovanni Tulipano
- Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Italy.
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17
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Vella V, Malaguarnera R, Nicolosi ML, Palladino C, Spoleti C, Massimino M, Vigneri P, Purrello M, Ragusa M, Morrione A, Belfiore A. Discoidin domain receptor 1 modulates insulin receptor signaling and biological responses in breast cancer cells. Oncotarget 2018; 8:43248-43270. [PMID: 28591735 PMCID: PMC5522143 DOI: 10.18632/oncotarget.18020] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 04/14/2017] [Indexed: 12/21/2022] Open
Abstract
The fetal isoform A of the insulin receptor (IR-A) is frequently overexpressed in a variety of malignancies including breast cancer. IR overexpression has a recognized role in cancer progression and resistance to anticancer therapies. In particular, IR-A has a peculiar mitogenic potential and is activated not only by insulin but also by IGF-2. Previously, we identified discoidin domain receptor 1 (DDR1) as a new IR-A interacting protein. DDR1, a non-integrin collagen tyrosine kinase receptor, is overexpressed in several malignancies and plays a role in cancer progression and metastasis. We now evaluated whether DDR1 is able to exert a role in breast cancer biology by functionally cross-talking with IR. In MCF-7 human breast cancer cells, IR and DDR1 co-immunoprecipitated and co-localized after insulin or IGF-2 stimulation. In a panel of breast cancer cells, DDR1 knockdown by specific siRNAs markedly inhibited IR downstream signaling as well as proliferation, migration and colony formation in response to insulin and IGF-2. These effects were accompanied by reduction of IR protein and mRNA expression, which involved both transcriptional and post-transcriptional effects. DDR1 overexpression elicited opposite effects. Bioinformatics analysis of public domain databases showed that IR and DDR1 co-expression significantly correlates with several clinically relevant histopathological and molecular features of human breast carcinomas. These findings demonstrate that, in human breast cancer cells, DDR1 regulates IR expression and ligand dependent biological actions. This novel functional crosstalk is likely clinically relevant and may become a new molecular target in breast cancer.
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Affiliation(s)
- Veronica Vella
- School of Motor Sciences, Faculty of Human and Social Sciences, Kore University of Enna, Enna, Italy
| | - Roberta Malaguarnera
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Maria Luisa Nicolosi
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Chiara Palladino
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Cristina Spoleti
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Michele Massimino
- Department of Clinical and Experimental Medicine, Faculty of Medicine, University of Catania, Catania, Italy
| | - Paolo Vigneri
- Department of Clinical and Experimental Medicine, Faculty of Medicine, University of Catania, Catania, Italy
| | - Michele Purrello
- Department of Biomedical and Biotechnological Sciences, Unit of BioMolecular, Genome, and Complex System BioMedicine, University of Catania, Catania, Italy
| | - Marco Ragusa
- Department of Biomedical and Biotechnological Sciences, Unit of BioMolecular, Genome, and Complex System BioMedicine, University of Catania, Catania, Italy
| | - Andrea Morrione
- Department of Urology and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Antonino Belfiore
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
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18
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Wang ZS, Huang HR, Zhang LY, Kim S, He Y, Li DL, Farischon C, Zhang K, Zheng X, Du ZY, Goodin S. Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells in Vitro and in Vivo. Biol Pharm Bull 2018; 40:1247-1254. [PMID: 28769006 DOI: 10.1248/bpb.b17-00077] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Metformin is a commonly used drug for the treatment of type II diabetes and atorvastatin is the most prescribed cholesterol-lowering statin. The present study investigated the effects and mechanisms of metformin and atorvastatin in combination on human prostate cancer cells cultured in vitro and grown as xenograft tumor in vivo. Metformin in combination with atorvastatin had stronger effects on growth inhibition and apoptosis in PC-3 cells than either drug alone. The combination also potently inhibited cell migration and the formation of tumorspheres. Metformin and atorvastatin in combination had a potent inhibitory effect on nuclear factor-kappaB (NF-κB) activity and caused strong decreases in the expression of its downstream anti-apoptotic gene Survivin. Moreover, strong decreases in the levels of phospho-Akt and phosphor-extracellular signal-regulated kinase (Erk)1/2 were found in the cells treated with the combination. The in vivo study showed that treatment of severe combined immunodeficient (SCID) mice with metformin or atorvastatin alone resulted in moderate inhibition of tumor growth while the combination strongly inhibited the growth of the tumors. Results of the present study indicate the combination of metformin and atorvastatin may be an effective strategy for inhibiting the growth of prostate cancer and should be evaluated clinically.
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Affiliation(s)
- Zhen-Shi Wang
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology
| | - Hua-Rong Huang
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology
| | - Lan-Yue Zhang
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology
| | - Seungkee Kim
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers
| | - Yan He
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology
| | - Dong-Li Li
- Department of Chemical and Environmental Engineering, Wuyi University
| | - Chelsea Farischon
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers
| | - Kun Zhang
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology.,Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers
| | - Xi Zheng
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers.,Rutgers Cancer Institute of New Jersey
| | - Zhi-Yun Du
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology
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19
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Penkert J, Ripperger T, Schieck M, Schlegelberger B, Steinemann D, Illig T. On metabolic reprogramming and tumor biology: A comprehensive survey of metabolism in breast cancer. Oncotarget 2018; 7:67626-67649. [PMID: 27590516 PMCID: PMC5341901 DOI: 10.18632/oncotarget.11759] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 08/25/2016] [Indexed: 12/20/2022] Open
Abstract
Altered metabolism in tumor cells has been a focus of cancer research for as long as a century but has remained controversial and vague due to an inhomogeneous overall picture. Accumulating genomic, metabolomic, and lastly panomic data as well as bioenergetics studies of the past few years enable a more comprehensive, systems-biologic approach promoting deeper insight into tumor biology and challenging hitherto existing models of cancer bioenergetics. Presenting a compendium on breast cancer-specific metabolome analyses performed thus far, we review and compile currently known aspects of breast cancer biology into a comprehensive network, elucidating previously dissonant issues of cancer metabolism. As such, some of the aspects critically discussed in this review include the dynamic interplay or metabolic coupling between cancer (stem) cells and cancer-associated fibroblasts, the intratumoral and intertumoral heterogeneity and plasticity of cancer cell metabolism, the existence of distinct metabolic tumor compartments in need of separate yet simultaneous therapeutic targeting, the reliance of cancer cells on oxidative metabolism and mitochondrial power, and the role of pro-inflammatory, pro-tumorigenic stromal conditioning. Comprising complex breast cancer signaling networks as well as combined metabolomic and genomic data, we address metabolic consequences of mutations in tumor suppressor genes and evaluate their contribution to breast cancer predisposition in a germline setting, reasoning for distinct personalized preventive and therapeutic measures. The review closes with a discussion on central root mechanisms of tumor cell metabolism and rate-limiting steps thereof, introducing essential strategies for therapeutic targeting.
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Affiliation(s)
- Judith Penkert
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Tim Ripperger
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany
| | | | | | - Doris Steinemann
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Thomas Illig
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany.,Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
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20
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Deng Y, Ma W. Metformin inhibits HaCaT cell viability via the miR-21/PTEN/Akt signaling pathway. Mol Med Rep 2017; 17:4062-4066. [PMID: 29286158 DOI: 10.3892/mmr.2017.8364] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 06/26/2017] [Indexed: 11/06/2022] Open
Abstract
Substantial preclinical evidence has indicated out a direct anti‑proliferation effect of metformin on various solid tumors; however, further and more detailed exploration into its molecular mechanism remains to be performed. The present study aimed to investigate the effect of metformin on cell viability and its underlying mechanism, in the cultured human skin keratinocyte cell line, HaCaT. In addition, it aimed to clarify the role of the microRNA-21(miR-21)/phosphatase and tensin homolog (PTEN)/AKT serine/threonine kinase 1 (Akt) signaling pathway, which has been hypothesized to be involved in the molecular mechanism of this drug. Cell Counting Kit‑8 assays were used to assess the impact of metformin on cell viability; reverse transcription‑quantitative polymerase chain reaction was used to quantify the expression of miR‑21; western blotting was used to monitor the expression level of PTEN and Akt proteins. In addition, miR‑21 expression levels were artificially manipulated in HaCaT cells using a miR‑21 inhibitor in order to observe the subsequent expression changes of miR‑21 targets and alterations in cell viability. The results indicated that metformin suppressed HaCaT cell growth in a dose‑ and time‑dependent manner (P<0.05). Metformin treatment downregulated miR‑21 expression (t=‑8.903, P<0.05). Following transfection with the miR‑21 inhibitor, HaCaT cell growth was significantly slower than in the control groups (P<0.05). In addition, reduced miR‑21 levels results in significantly increased PTEN protein expression levels and reduced Akt protein expression levels compared with control (P<0.05). Metformin was, therefore, concluded to inhibit HaCaT cell growth in a time‑and dose‑dependent manner, and the miR‑21/PTEN/Akt signaling pathway may serve a crucial role in the molecular mechanism of metformin's effect on HaCaT cells. Therefore the present study presents an advanced insight into the potential inhibitory effect of metformin on tumor cells.
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Affiliation(s)
- Yue Deng
- Hypertension Center of Fuwai Hospital, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100006, P.R. China
| | - Weiyuan Ma
- Department of Dermatology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
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21
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Gonzalez-Menendez P, Hevia D, Mayo JC, Sainz RM. The dark side of glucose transporters in prostate cancer: Are they a new feature to characterize carcinomas? Int J Cancer 2017; 142:2414-2424. [DOI: 10.1002/ijc.31165] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 11/01/2017] [Accepted: 11/15/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Pedro Gonzalez-Menendez
- Department of Morphology and Cell Biology; Redox Biology Unit, University Institute of Oncology of Asturias (IUOPA). University of Oviedo. Facultad de Medicina.; Oviedo Spain
| | - David Hevia
- Department of Morphology and Cell Biology; Redox Biology Unit, University Institute of Oncology of Asturias (IUOPA). University of Oviedo. Facultad de Medicina.; Oviedo Spain
| | - Juan C. Mayo
- Department of Morphology and Cell Biology; Redox Biology Unit, University Institute of Oncology of Asturias (IUOPA). University of Oviedo. Facultad de Medicina.; Oviedo Spain
| | - Rosa M. Sainz
- Department of Morphology and Cell Biology; Redox Biology Unit, University Institute of Oncology of Asturias (IUOPA). University of Oviedo. Facultad de Medicina.; Oviedo Spain
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22
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Gong J, Kelekar G, Shen J, Shen J, Kaur S, Mita M. The expanding role of metformin in cancer: an update on antitumor mechanisms and clinical development. Target Oncol 2017; 11:447-67. [PMID: 26864078 DOI: 10.1007/s11523-016-0423-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Metformin has been used for nearly a century to treat type 2 diabetes mellitus. Epidemiologic studies first identified the association between metformin and reduced risk of several cancers. The anticancer mechanisms of metformin involve both indirect or insulin-dependent pathways and direct or insulin-independent pathways. Preclinical studies have demonstrated metformin's broad anticancer activity across a spectrum of malignancies. Prospective clinical trials involving metformin in the chemoprevention and treatment of cancer now number in the hundreds. We provide an update on the anticancer mechanisms of metformin and review the results thus far available from prospective clinical trials investigating metformin's efficacy in cancer.
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Affiliation(s)
- Jun Gong
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Gauri Kelekar
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - James Shen
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - John Shen
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Sukhpreet Kaur
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Monica Mita
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. .,Experimental Therapeutics Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, SCCT Mezzanine MS 35, Los Angeles, CA, 90048, USA.
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23
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Zingales V, Distefano A, Raffaele M, Zanghi A, Barbagallo I, Vanella L. Metformin: A Bridge between Diabetes and Prostate Cancer. Front Oncol 2017; 7:243. [PMID: 29075616 PMCID: PMC5641539 DOI: 10.3389/fonc.2017.00243] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 09/25/2017] [Indexed: 12/12/2022] Open
Abstract
Prostate cancer (PCa) has become the most frequent type of cancer in men. Recent data suggest that diabetic patients taking metformin have a lower incidence of certain cancer, including PCa. Metformin is the most common drug used in type II diabetes mellitus; its use has been shown to lower the incidence of several cancers, although there are ambiguous data about the anticancer activity of metformin. A large number of studies examined the potential antineoplastic mechanism of metformin although it is not still completely understood. This review summarizes the literature concerning the effects of metformin on PCa cells, highlighting its numerous mechanisms of action through which it can act. We analyze the possible causes of the discordances regarding the impact of metformin on risk of PCa; we discuss the latest findings in this field, suggesting that metformin may have a future role in the management of PCa both as monotherapy and in combination with other drugs.
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Affiliation(s)
- Veronica Zingales
- Department of Drug Science, Biochemistry Section, University of Catania, Catania, Italy
| | - Alfio Distefano
- Department of Drug Science, Biochemistry Section, University of Catania, Catania, Italy
| | - Marco Raffaele
- Department of Drug Science, Biochemistry Section, University of Catania, Catania, Italy
| | - Antonio Zanghi
- Department of Surgery, Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele, Catania, Italy
| | - Ignazio Barbagallo
- Department of Drug Science, Biochemistry Section, University of Catania, Catania, Italy
| | - Luca Vanella
- Department of Drug Science, Biochemistry Section, University of Catania, Catania, Italy
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24
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Mina A, Yoder R, Sharma P. Targeting the androgen receptor in triple-negative breast cancer: current perspectives. Onco Targets Ther 2017; 10:4675-4685. [PMID: 29033586 PMCID: PMC5614778 DOI: 10.2147/ott.s126051] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype associated with frequent recurrence and metastasis. Unlike hormone receptor-positive subtypes, treatment of TNBC is currently limited by the lack of clinically available targeted therapies. Androgen signaling is necessary for normal breast development, and its dysregulation has been implicated in breast tumorigenesis. In recent years, gene expression studies have identified a subset of TNBC that is enriched for androgen receptor (AR) signaling. Interference with androgen signaling in TNBC is promising, and AR-inhibiting drugs have shown antitumorigenic activity in preclinical and proof of concept clinical studies. Recent advances in our understanding of androgenic signaling in TNBC, along with the identification of interacting pathways, are allowing development of the next generation of clinical trials with AR inhibitors. As novel AR-targeting agents are developed and evaluated in clinical trials, it is equally important to establish a robust set of biomarkers for identification of TNBC tumors that are most likely to respond to AR inhibition.
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Affiliation(s)
- Alain Mina
- Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Westwood
| | - Rachel Yoder
- University of Kansas Cancer Center, Kansas City, KS, USA
| | - Priyanka Sharma
- Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Westwood
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Lei Y, Yi Y, Liu Y, Liu X, Keller ET, Qian CN, Zhang J, Lu Y. Metformin targets multiple signaling pathways in cancer. CHINESE JOURNAL OF CANCER 2017; 36:17. [PMID: 28126011 PMCID: PMC5270304 DOI: 10.1186/s40880-017-0184-9] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 06/21/2016] [Indexed: 12/20/2022]
Abstract
Metformin, an inexpensive and well-tolerated oral agent commonly used in the first-line treatment of type 2 diabetes, has become the focus of intense research as a candidate anticancer agent. Here, we discuss the potential of metformin in cancer therapeutics, particularly its functions in multiple signaling pathways, including AMP-activated protein kinase, mammalian target of rapamycin, insulin-like growth factor, c-Jun N-terminal kinase/mitogen-activated protein kinase (p38 MAPK), human epidermal growth factor receptor-2, and nuclear factor kappaB pathways. In addition, cutting-edge targeting of cancer stem cells by metformin is summarized.
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Affiliation(s)
- Yong Lei
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, 530021, Guangxi, P. R. China.,Center for Translational Medicine, Guangxi Medical University, 14th Floor, Pharmacology and Biomedical Sciences Building, No. 22 Shuangyong Road, Nanning, 530021, Guangxi, P. R. China
| | - Yanhua Yi
- School for International Education, Guangxi Medical University, Nanning, 530021, Guangxi, P. R. China
| | - Yang Liu
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, 530021, Guangxi, P. R. China.,Center for Translational Medicine, Guangxi Medical University, 14th Floor, Pharmacology and Biomedical Sciences Building, No. 22 Shuangyong Road, Nanning, 530021, Guangxi, P. R. China
| | - Xia Liu
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, 530021, Guangxi, P. R. China.,Center for Translational Medicine, Guangxi Medical University, 14th Floor, Pharmacology and Biomedical Sciences Building, No. 22 Shuangyong Road, Nanning, 530021, Guangxi, P. R. China
| | - Evan T Keller
- Department of Urology and Pathology, School of Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Chao-Nan Qian
- Department of Nasopharyngeal Carcinoma, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China
| | - Jian Zhang
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, 530021, Guangxi, P. R. China. .,Center for Translational Medicine, Guangxi Medical University, 14th Floor, Pharmacology and Biomedical Sciences Building, No. 22 Shuangyong Road, Nanning, 530021, Guangxi, P. R. China. .,Department of Urology and Pathology, School of Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
| | - Yi Lu
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, 530021, Guangxi, P. R. China. .,Center for Translational Medicine, Guangxi Medical University, 14th Floor, Pharmacology and Biomedical Sciences Building, No. 22 Shuangyong Road, Nanning, 530021, Guangxi, P. R. China.
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Vella V, Nicolosi ML, Giuliano S, Bellomo M, Belfiore A, Malaguarnera R. PPAR-γ Agonists As Antineoplastic Agents in Cancers with Dysregulated IGF Axis. Front Endocrinol (Lausanne) 2017; 8:31. [PMID: 28275367 PMCID: PMC5319972 DOI: 10.3389/fendo.2017.00031] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 02/06/2017] [Indexed: 12/13/2022] Open
Abstract
It is now widely accepted that insulin resistance and compensatory hyperinsulinemia are associated to increased cancer incidence and mortality. Moreover, cancer development and progression as well as cancer resistance to traditional anticancer therapies are often linked to a deregulation/overactivation of the insulin-like growth factor (IGF) axis, which involves the autocrine/paracrine production of IGFs (IGF-I and IGF-II) and overexpression of their cognate receptors [IGF-I receptor, IGF-insulin receptor (IR), and IR]. Recently, new drugs targeting various IGF axis components have been developed. However, these drugs have several limitations including the occurrence of insulin resistance and compensatory hyperinsulinemia, which, in turn, may affect cancer cell growth and survival. Therefore, new therapeutic approaches are needed. In this regard, the pleiotropic effects of peroxisome proliferator activated receptor (PPAR)-γ agonists may have promising applications in cancer prevention and therapy. Indeed, activation of PPAR-γ by thiazolidinediones (TZDs) or other agonists may inhibit cell growth and proliferation by lowering circulating insulin and affecting key pathways of the Insulin/IGF axis, such as PI3K/mTOR, MAPK, and GSK3-β/Wnt/β-catenin cascades, which regulate cancer cell survival, cell reprogramming, and differentiation. In light of these evidences, TZDs and other PPAR-γ agonists may be exploited as potential preventive and therapeutic agents in tumors addicted to the activation of IGF axis or occurring in hyperinsulinemic patients. Unfortunately, clinical trials using PPAR-γ agonists as antineoplastic agents have reached conflicting results, possibly because they have not selected tumors with overactivated insulin/IGF-I axis or occurring in hyperinsulinemic patients. In conclusion, the use of PPAR-γ agonists in combined therapies of IGF-driven malignancies looks promising but requires future developments.
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Affiliation(s)
- Veronica Vella
- Scienze delle Attività Motorie e Sportive, University Kore, Enna, Italy
| | - Maria Luisa Nicolosi
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Stefania Giuliano
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Maria Bellomo
- Scienze delle Attività Motorie e Sportive, University Kore, Enna, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
- *Correspondence: Antonino Belfiore,
| | - Roberta Malaguarnera
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
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Biernacka KM, Persad RA, Bahl A, Gillatt D, Holly JMP, Perks CM. Hyperglycaemia-induced resistance to Docetaxel is negated by metformin: a role for IGFBP-2. Endocr Relat Cancer 2017; 24:17-30. [PMID: 27754854 PMCID: PMC5118949 DOI: 10.1530/erc-16-0095] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 10/17/2016] [Indexed: 12/13/2022]
Abstract
The incidence of many common cancers varies between different populations and appears to be affected by a Western lifestyle. Highly proliferative malignant cells require sufficient levels of nutrients for their anabolic activity. Therefore, targeting genes and pathways involved in metabolic pathways could yield future therapeutics. A common pathway implicated in energetic and nutritional requirements of a cell is the LKB1/AMPK pathway. Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes by targeting this pathway. We investigated the effect of metformin on prostate cancer cell lines and evaluated its mechanism of action using DU145, LNCaP, PC3 and VCaP prostate cancer cell lines. Trypan blue dye-exclusion assay was used to assess levels of cell death. Western immunoblotting was used to determine the abundance of proteins. Insulin-like growth factor-binding protein-2 (IGFBP-2) and AMPK genes were silenced using siRNA. Effects on cell morphology were visualised using microscopy. IGFBP-2 gene expression was assessed using real-time RT-PCR. With DU145 and LNCaP cells metformin alone induced cell death, but this was reduced in hyperglycaemic conditions. Hyperglycaemia also reduced the sensitivity to Docetaxel, but this was countered by co-treatment with metformin. LKB1 was required for the activation of AMPK but was not essential to mediate the induction of cell death. An alternative pathway by which metformin exerted its action was through downregulation of IGFBP-2 in DU145 and LNCaP cells, independently of AMPK. This finding could have important implications in relation to therapeutic strategies in prostate cancer patients presenting with diabetes.
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Affiliation(s)
- K M Biernacka
- IGFs & Metabolic Endocrinology GroupSchool of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK
| | - R A Persad
- Department of UrologySouthmead Hospital, Bristol, UK
| | - A Bahl
- Department of Clinical OncologyBristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK
| | - D Gillatt
- Department of UrologySouthmead Hospital, Bristol, UK
| | - J M P Holly
- IGFs & Metabolic Endocrinology GroupSchool of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK
| | - C M Perks
- IGFs & Metabolic Endocrinology GroupSchool of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK
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Malaguarnera R, Vella V, Nicolosi ML, Belfiore A. Insulin Resistance: Any Role in the Changing Epidemiology of Thyroid Cancer? Front Endocrinol (Lausanne) 2017; 8:314. [PMID: 29184536 PMCID: PMC5694441 DOI: 10.3389/fendo.2017.00314] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 10/30/2017] [Indexed: 12/13/2022] Open
Abstract
In the past few decades, the incidence of thyroid cancer (TC), namely of its papillary hystotype (PTC), has shown a steady increase worldwide, which has been attributed at least in part to the increasing diagnosis of early stage tumors. However, some evidence suggests that environmental and lifestyle factors can also play a role. Among the potential risk factors involved in the changing epidemiology of TC, particular attention has been drawn to insulin-resistance and related metabolic disorders, such as obesity, type 2 diabetes, and metabolic syndrome, which have been also rapidly increasing worldwide due to widespread dietary and lifestyle changes. In accordance with this possibility, various epidemiological studies have indeed gathered substantial evidence that insulin resistance-related metabolic disorders might be associated with an increased TC risk either through hyperinsulinemia or by affecting other TC risk factors including iodine deficiency, elevated thyroid stimulating hormone, estrogen-dependent signaling, chronic autoimmune thyroiditis, and others. This review summarizes the current literature evaluating the relationship between metabolic disorders characterized by insulin resistance and the risk for TC as well as the possible underlying mechanisms. The potential implications of such association in TC prevention and therapy are discussed.
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Affiliation(s)
- Roberta Malaguarnera
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Veronica Vella
- School of Human and Social Sciences, “Kore” University of Enna, Enna, Italy
- *Correspondence: Veronica Vella, ; Antonino Belfiore,
| | - Maria Luisa Nicolosi
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
- *Correspondence: Veronica Vella, ; Antonino Belfiore,
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Tong D, Liu Q, Liu G, Xu J, Lan W, Jiang Y, Xiao H, Zhang D, Jiang J. Metformin inhibits castration-induced EMT in prostate cancer by repressing COX2/PGE2/STAT3 axis. Cancer Lett 2016; 389:23-32. [PMID: 28043910 DOI: 10.1016/j.canlet.2016.12.031] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 12/21/2016] [Accepted: 12/22/2016] [Indexed: 12/17/2022]
Abstract
Castration is the standard therapeutic treatment for advanced prostate cancer but with limited benefit due to the profound relapse and metastasis. Activation of inflammatory signaling pathway and initiation of epithelial-mesenchymal transition (EMT) are closely related to drug resistance, tumor relapseas well as metastasis. In this study, we demonstrated that metformin is capable of inhibiting prostate cancer cell migration and invasion by repressing EMT evidenced by downregulating the mesenchymal markers N-cadherin, Vimentin, and Twist and upregulating the epithelium E-cadherin. These effects have also been observed in our animal model as well as prostate cancer patients. In addition, we showed the effects of metformin on the expression of genes involved in EMT through repressing the levels of COX2, PGE2 and phosphorylated STAT3. Furthermore, inactivating COX2 abolishes metformin's regulatory effects and exogenously administered PGE2 is capable of enhancing STAT3 phosphorylation and expression of EMT biomarker. We propose that metformin represses prostate cancer EMT and metastasis through targeting the COX2/PGE2/STAT3 axis. These findings suggest that metformin by itself or in combination with other anticancer drugs could be used as an anti-metastasis therapy.
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Affiliation(s)
- Dali Tong
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China
| | - Qiuli Liu
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China
| | - Gaolei Liu
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China
| | - Jing Xu
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China
| | - Weihua Lan
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China
| | - Yao Jiang
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China
| | - Hualiang Xiao
- Department of Pathology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China
| | - Dianzheng Zhang
- Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USA
| | - Jun Jiang
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
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Hankinson SJ, Fam M, Patel NN. A review for clinicians: Prostate cancer and the antineoplastic properties of metformin. Urol Oncol 2016; 35:21-29. [PMID: 27836248 DOI: 10.1016/j.urolonc.2016.10.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 08/11/2016] [Accepted: 10/07/2016] [Indexed: 01/05/2023]
Abstract
OBJECTIVES Metformin has numerous antineoplastic effects including an AMP-activated protein kinase-dependent mechanism, AMP-activated protein kinase-independent mechanisms, alteration of insulin and insulin-like growth factor signaling pathways, and suppression of androgen signaling pathways that trigger prostate cancer growth and proliferation. In contrast to other malignancies that are associated with increased incidence among patients with obesity and type II diabetes mellitus (T2DM), epidemiological studies suggest that obesity and T2DM may impart a protective effect on prostate cancer incidence by creating a set of metabolic conditions that lower androgen levels. METHODS AND MATERIALS The PubMed and Web of Science databases were searched using the terms "prostate cancer," "metformin," "antineoplastic," "antitumorigenic," and "diabetes" up to the first week of August 2016. Articles regarding metformin's antineoplastic properties on prostate cancer were reviewed. RESULTS Treating T2DM with metformin may reverse the metabolic conditions that suppress androgen levels, thereby enabling higher levels of androgens to stimulate prostate growth, proliferation, and tumorigenesis. Thus, the antineoplastic properties of metformin may not be appreciable in the early stages of prostate cancer development because metformin corrects for the metabolic conditions of T2DM that impart a protective effect on prostate cancer. These findings, although inconclusive, do not support the use of metformin as a preventive agent for prostate cancer. However, the future appears bright for metformin as either a monotherapy or an adjunct to androgen deprivation therapy, external-beam radiation therapy, prostatectomy, or chemotherapy. Support for this includes meta-analyses that suggest a mortality benefit to patients with prostate cancer on metformin, a clinical trial that demonstrates metformin leads to significant improvement in metabolic syndrome parameters for patients with prostate cancer on androgen deprivation therapy, and a clinical trial that shows metformin has modest activity in the treatment of some patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. CONCLUSIONS This review summarizes the literature regarding the antineoplastic mechanisms, clinical implications, and future trajectory of clinical research for metformin in prostate cancer.
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Affiliation(s)
| | - Mina Fam
- Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Nitin N Patel
- Division of Urology, Department of Surgery, Rutgers New Jersey Medical School, Newark, NJ
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Sayyid RK, Fleshner NE. Potential role for metformin in urologic oncology. Investig Clin Urol 2016; 57:157-64. [PMID: 27195314 PMCID: PMC4869570 DOI: 10.4111/icu.2016.57.3.157] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Accepted: 04/22/2016] [Indexed: 12/13/2022] Open
Abstract
Metformin is one of the most commonly used drugs worldwide. It is currently considered first-line pharmacological agent for management of diabetes mellitus type 2. Recent studies have suggested that metformin may have further benefits, especially in the field of urologic oncology. Use of metformin has been shown to be associated with decreased incidence and improved outcomes of prostate, bladder, and kidney cancer. These studies suggest that metformin does have a future role in the prevention and management of urologic malignancies. In this review, we will discuss the latest findings in this field and its implications on the management of urologic oncology patients.
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Affiliation(s)
| | - Neil Eric Fleshner
- Department of Urology, Princess Margaret Cancer Centre, Toronto, ON, Canada
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Metformin Attenuates Testosterone-Induced Prostatic Hyperplasia in Rats: A Pharmacological Perspective. Sci Rep 2015; 5:15639. [PMID: 26492952 PMCID: PMC4616049 DOI: 10.1038/srep15639] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 10/01/2015] [Indexed: 12/15/2022] Open
Abstract
Benign prostatic hyperplasia (BPH) is uncontrolled proliferation of prostate tissue. Metformin, a widely prescribed anti-diabetic agent, possesses anticancer activity through induction of apoptotic signaling and cell cycle arrest. This study aimed to investigate the protective effect of metformin against experimentally-induced BPH in rats. Treatment with 500 and 1000 mg/kg metformin orally for 14 days significantly inhibited testosterone-mediated increase in the prostate weight & prostate index (prostate weight/body weight [mg/g]) and attenuated the pathological alterations induced by testosterone. Mechanistically, metformin significantly protected against testosterone-induced elevation of estrogen receptor-α (ER-α) and decrease of estrogen receptor-β (ER-β) expression, with no significant effect of androgen receptor (AR) and 5α-reductase expression. It decreased mRNA expression of IGF-1 and IGF-1R and protein expression ratio of pAkt/total Akt induced by testosterone. Furthermore, it significantly ameliorated testosterone–induced reduction of mRNA expression Bax/Bcl-2 ratio, P21 and phosphatase and tensin homolog (PTEN) and AMPK [PT-172] activity. In conclusion, these findings elucidate the effectiveness of metformin in preventing testosterone-induced BPH in rats. These results could be attributed, at least partly, to its ability to enhance expression ratio of ER-β/ER-α, decrease IGF-1, IGF-1R and pAkt expressions, increase P21, PTEN, Bax/Bcl-2 expressions and activate AMPK with a subsequent inhibition of prostate proliferation.
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Tsutsumi Y, Nomiyama T, Kawanami T, Hamaguchi Y, Terawaki Y, Tanaka T, Murase K, Motonaga R, Tanabe M, Yanase T. Combined Treatment with Exendin-4 and Metformin Attenuates Prostate Cancer Growth. PLoS One 2015; 10:e0139709. [PMID: 26439622 PMCID: PMC4595004 DOI: 10.1371/journal.pone.0139709] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Accepted: 09/16/2015] [Indexed: 01/06/2023] Open
Abstract
INTRODUCTION Recently, the pleiotropic benefits of incretin-based therapy have been reported. We have previously reported that Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, attenuates prostate cancer growth. Metformin is known for its anti-cancer effect. Here, we examined the anti-cancer effect of Exendin-4 and metformin using a prostate cancer model. METHODS Prostate cancer cells were treated with Exendin-4 and/or metformin. Cell proliferation was quantified by growth curves and 5-bromo-2'-deoxyuridine (BrdU) assay. TUNEL assay and AMP-activated protein kinase (AMPK) phosphorylation were examined in LNCaP cells. For in vivo experiments, LNCaP cells were transplanted subcutaneously into the flank region of athymic mice, which were then treated with Exendin-4 and/or metformin. TUNEL assay and immunohistochemistry were performed on tumors. RESULTS Exendin-4 and metformin additively decreased the growth curve, but not the migration, of prostate cancer cells. The BrdU assay revealed that both Exendin-4 and metformin significantly decreased prostate cancer cell proliferation. Furthermore, metformin, but not Exendin-4, activated AMPK and induced apoptosis in LNCaP cells. The anti-proliferative effect of metformin was abolished by inhibition or knock down of AMPK. In vivo, Exendin-4 and metformin significantly decreased tumor size, and further significant tumor size reduction was observed after combined treatment. Immunohistochemistry on tumors revealed that the P504S and Ki67 expression decreased by Exendin-4 and/or metformin, and that metformin increased phospho-AMPK expression and the apoptotic cell number. CONCLUSION These data suggest that Exendin-4 and metformin attenuated prostate cancer growth by inhibiting proliferation, and that metformin inhibited proliferation by inducing apoptosis. Combined treatment with Exendin-4 and metformin attenuated prostate cancer growth more than separate treatments.
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Affiliation(s)
- Yoko Tsutsumi
- Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814–0180, Japan
| | - Takashi Nomiyama
- Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814–0180, Japan
| | - Takako Kawanami
- Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814–0180, Japan
| | - Yuriko Hamaguchi
- Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814–0180, Japan
| | - Yuichi Terawaki
- Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814–0180, Japan
| | - Tomoko Tanaka
- Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814–0180, Japan
| | - Kunitaka Murase
- Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814–0180, Japan
| | - Ryoko Motonaga
- Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814–0180, Japan
| | - Makito Tanabe
- Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814–0180, Japan
| | - Toshihiko Yanase
- Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814–0180, Japan
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Joshi G, Singh PK, Negi A, Rana A, Singh S, Kumar R. Growth factors mediated cell signalling in prostate cancer progression: Implications in discovery of anti-prostate cancer agents. Chem Biol Interact 2015; 240:120-33. [PMID: 26297992 DOI: 10.1016/j.cbi.2015.08.009] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 07/16/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022]
Abstract
Cancer is one of the leading causes of mortality amongst world's population, in which prostate cancer is one of the most encountered malignancies among men. Globally, it is the sixth leading cause of cancer-related death in men. Prostate cancer is more prevalent in the developed world and is increasing at alarming rates in the developing countries. Prostate cancer is mostly a very sluggish progressing disease, caused by the overproduction of steroidal hormones like dihydrotestosterone or due to over-expression of enzymes such as 5-α-reductase. Various studies have revealed that growth factors play a crucial role in the progression of prostate cancer as they act either by directly elevating the level of steroidal hormones or upregulating enzyme efficacy by the active feedback mechanism. Presently, treatment options for prostate cancer include radiotherapy, surgery and chemotherapy. If treatment is done with prevailing traditional chemotherapy; it leads to resistance and development of androgen-independent prostate cancer that further complicates the situation with no cure option left. The current review article is an attempt to cover and establish an understanding of some major signalling pathways intervened through survival factors (IGF-1R), growth factors (TGF-α, EGF), Wnt, Hedgehog, interleukin, cytokinins and death factor receptor which are frequently dysregulated in prostate cancer. This will enable the researchers to design and develop better therapeutic strategies targeting growth factors and their cross talks mediated prostate cancer cell signalling.
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Affiliation(s)
- Gaurav Joshi
- Laboratory for Drug Design and Synthesis, Centre for Pharmaceutical Sciences and Natural Products, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151001, India
| | - Pankaj Kumar Singh
- Laboratory for Drug Design and Synthesis, Centre for Pharmaceutical Sciences and Natural Products, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151001, India
| | - Arvind Negi
- Laboratory for Drug Design and Synthesis, Centre for Pharmaceutical Sciences and Natural Products, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151001, India
| | - Anil Rana
- Laboratory for Drug Design and Synthesis, Centre for Pharmaceutical Sciences and Natural Products, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151001, India
| | - Sandeep Singh
- Centre for Genetic Diseases and Molecular Medicine, School of Emerging Life Science Technologies, Central University of Punjab, Bathinda 151001, India
| | - Raj Kumar
- Laboratory for Drug Design and Synthesis, Centre for Pharmaceutical Sciences and Natural Products, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151001, India.
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New Insights for Oxidative Stress and Diabetes Mellitus. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:875961. [PMID: 26064426 PMCID: PMC4443788 DOI: 10.1155/2015/875961] [Citation(s) in RCA: 149] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Accepted: 04/15/2015] [Indexed: 12/12/2022]
Abstract
The release of reactive oxygen species (ROS) and the generation of oxidative stress are considered critical factors for the pathogenesis of diabetes mellitus (DM), a disorder that is growing in prevalence and results in significant economic loss. New therapeutic directions that address the detrimental effects of oxidative stress may be especially warranted to develop effective care for the millions of individuals that currently suffer from DM. The mechanistic target of rapamycin (mTOR), silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), and Wnt1 inducible signaling pathway protein 1 (WISP1) are especially justified to be considered treatment targets for DM since these pathways can address the complex relationship between stem cells, trophic factors, impaired glucose tolerance, programmed cell death pathways of apoptosis and autophagy, tissue remodeling, cellular energy homeostasis, and vascular biology that greatly impact the biology and disease progression of DM. The translation and development of these pathways into viable therapies will require detailed understanding of their proliferative nature to maximize clinical efficacy and limit adverse effects that have the potential to lead to unintended consequences.
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Jurmeister S, Ramos-Montoya A, Neal DE, Fryer LGD. Transcriptomic analysis reveals inhibition of androgen receptor activity by AMPK in prostate cancer cells. Oncotarget 2015; 5:3785-99. [PMID: 25003216 PMCID: PMC4116520 DOI: 10.18632/oncotarget.1997] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Metabolic alterations contribute to prostate cancer development and progression; however, the role of the central metabolic regulator AMP-activated protein kinase (AMPK) remains controversial. The androgen receptor (AR), a key driver of prostate cancer, regulates prostate cancer cell metabolism by driving the expression of a network of metabolic genes and activates AMPK through increasing the expression of one of its upstream kinases. To more clearly define the role of AMPK in prostate cancer, we performed expression profiling following pharmacologic activation of this kinase. We found that genes down-regulated upon AMPK activation were over-expressed in prostate cancer, consistent with a tumour suppressive function of AMPK. Strikingly, we identified the AR as one of the most significantly enriched transcription factors mediating gene expression changes downstream of AMPK signalling in prostate cancer cells. Activation of AMPK inhibited AR transcriptional activity and reduced androgen-dependent expression of known AR target genes. Conversely, knock-down of AMPK increased AR activity. Modulation of AR expression could not explain these effects. Instead, we observed that activation of AMPK reduced nuclear localisation of the AR. We thus propose the presence of a negative feedback loop in prostate cancer cells whereby AR activates AMPK and AMPK feeds back to limit AR-driven transcription.
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Affiliation(s)
- Sarah Jurmeister
- Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
| | | | | | - Lee G D Fryer
- Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
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Kato H, Sekine Y, Furuya Y, Miyazawa Y, Koike H, Suzuki K. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor. Biochem Biophys Res Commun 2015; 461:115-21. [PMID: 25862373 DOI: 10.1016/j.bbrc.2015.03.178] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 03/31/2015] [Indexed: 11/30/2022]
Abstract
Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment.
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Affiliation(s)
- Haruo Kato
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
| | - Yoshitaka Sekine
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Yosuke Furuya
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Yoshiyuki Miyazawa
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Hidekazu Koike
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Kazuhiro Suzuki
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
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Maiese K. mTOR: Driving apoptosis and autophagy for neurocardiac complications of diabetes mellitus. World J Diabetes 2015; 6:217-224. [PMID: 25789103 PMCID: PMC4360415 DOI: 10.4239/wjd.v6.i2.217] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Revised: 12/10/2014] [Accepted: 01/19/2015] [Indexed: 02/05/2023] Open
Abstract
The World Health Organization estimates that diabetes mellitus (DM) will become the seventh leading cause of death during the next two decades. DM affects approximately 350 million individuals worldwide and additional millions that remain undiagnosed are estimated to suffer from the complications of DM. Although the complications of DM can be seen throughout the body, the nervous, cardiac, and vascular systems can be significantly affected and lead to disorders that include cognitive loss, stroke, atherosclerosis, cardiac failure, and endothelial stem cell impairment. At the cellular level, oxidative stress is a significant determinant of cell fate during DM and leads to endoplasmic reticulum stress, mitochondrial dysfunction, apoptosis, and autophagy. Multiple strategies are being developed to combat the complications of DM, but it is the mechanistic target of rapamycin (mTOR) that is gaining interest in drug development circles especially for protective therapies that involve cytokines and growth factors such as erythropoietin. The pathways of mTOR linked to mTOR complex 1, mTOR complex 2, AMP activated protein kinase, and the hamartin (tuberous sclerosis 1)/tuberin (tuberous sclerosis 2) complex can ultimately influence neuronal, cardiac, and vascular cell survival during oxidant stress in DM through a fine interplay between apoptosis and autophagy. Further understanding of these mTOR regulated pathways should foster novel strategies for the complications of DM that impact millions of individuals with death and disability.
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Maiese K. Programming apoptosis and autophagy with novel approaches for diabetes mellitus. Curr Neurovasc Res 2015; 12:173-88. [PMID: 25742566 PMCID: PMC4380829 DOI: 10.2174/1567202612666150305110929] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 02/16/2015] [Accepted: 02/19/2015] [Indexed: 12/13/2022]
Abstract
According to the World Health Organization, diabetes mellitus (DM) in the year 2030 will be ranked the seventh leading cause of death in the world. DM impacts all systems of the body with oxidant stress controlling cell fate through endoplasmic reticulum stress, mitochondrial dysfunction, alterations in uncoupling proteins, and the induction of apoptosis and autophagy. Multiple treatment approaches are being entertained for DM with Wnt1 inducible signaling pathway protein 1 (WISP1), mechanistic target of rapamycin (mTOR), and silent mating type information regulation 2 homolog) 1 (S. cerevisiae) (SIRT1) generating significant interest as target pathways that can address maintenance of glucose homeostasis as well as prevention of cellular pathology by controlling insulin resistance, stem cell proliferation, and the programmed cell death pathways of apoptosis and autophagy. WISP1, mTOR, and SIRT1 can rely upon similar pathways such as AMP activated protein kinase as well as govern cellular metabolism through cytokines such as EPO and oral hypoglycemics such as metformin. Yet, these pathways require precise biological control to exclude potentially detrimental clinical outcomes. Further elucidation of the ability to translate the roles of WISP1, mTOR, and SIRT1 into effective clinical avenues offers compelling prospects for new therapies against DM that can benefit hundreds of millions of individuals throughout the globe.
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Affiliation(s)
- Kenneth Maiese
- MD, Cellular and Molecular Signaling, Newark, New Jersey 07101, USA.
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Maiese K. Cutting through the complexities of mTOR for the treatment of stroke. Curr Neurovasc Res 2014; 11:177-86. [PMID: 24712647 DOI: 10.2174/1567202611666140408104831] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Revised: 03/17/2014] [Accepted: 03/19/2014] [Indexed: 01/06/2023]
Abstract
On a global basis, at least 15 million individuals suffer some form of a stroke every year. Of these individuals, approximately 800,000 of these cerebrovascular events occur in the United States (US) alone. The incidence of stroke in the US has declined from the third leading cause of death to the fourth, a result that can be attributed to multiple factors that include improved vascular disease management, reduced tobacco use, and more rapid time to treatment in patients that are clinically appropriate to receive recombinant tissue plasminogen activator. However, treatment strategies for the majority of stroke patients are extremely limited and represent a critical void for care. A number of new therapeutic considerations for stroke are under consideration, but it is the mammalian target of rapamycin (mTOR) that is receiving intense focus as a potential new target for cerebrovascular disease. As part of the phosphoinositide 3-kinase (PI 3-K) and protein kinase B (Akt) cascade, mTOR is an essential component of mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) to govern cell death involving apoptosis, autophagy, and necroptosis, cellular metabolism, and gene transcription. Vital for the consideration of new therapeutic strategies for stroke is the ability to understand how the intricate and complex pathways of mTOR signaling sometimes lead to disparate clinical outcomes.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101, USA.
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Janssen JAMJL, Varewijck AJ. IGF-IR Targeted Therapy: Past, Present and Future. Front Endocrinol (Lausanne) 2014; 5:224. [PMID: 25566194 PMCID: PMC4275034 DOI: 10.3389/fendo.2014.00224] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 12/08/2014] [Indexed: 01/01/2023] Open
Abstract
The IGF-I receptor (IGF-IR) has been studied as an anti-cancer target. However, monotherapy trials with IGF-IR targeted antibodies or with IGF-IR specific tyrosine kinase inhibitors have, overall, been very disappointing in the clinical setting. This review discusses potential reasons why IGF-I R targeted therapy fails to inhibit growth of human cancers. It has become clear that intracellular signaling pathways are highly interconnected and complex instead of being linear and simple. One of the most potent candidates for failure of IGF-IR targeted therapy is the insulin receptor isoform A (IR-A). Activation of the IR-A by insulin-like growth factor-II (IGF-II) bypasses the IGF-IR and its inhibition. Another factor may be that anti-cancer treatment may reduce IGF-IR expression. IGF-IR blocking drugs may also induce hyperglycemia and hyperinsulinemia, which may further stimulate cell growth. In addition, circulating IGF-IRs may reduce therapeutic effects of IGF-IR targeted therapy. Nevertheless, it is still possible that the IGF-IR may be a useful adjuvant or secondary target for the treatment of human cancers. Development of functional inhibitors that affect the IGF-IR and IR-A may be necessary to overcome resistance and to make IGF-IR targeted therapy successful. Drugs that modify alternative downstream effects of the IGF-IR, so called "biasing agonists," should also be considered.
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Affiliation(s)
- Joseph A. M. J. L. Janssen
- Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, Netherlands
- *Correspondence: Joseph A. M. J. L. Janssen, Department of Internal Medicine, Erasmus MC, Room D-443, ‘s-Gravendijkwal 230, Rotterdam 3015 CE, Netherlands e-mail:
| | - Aimee J. Varewijck
- Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, Netherlands
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Bruchim I, Sarfstein R, Werner H. The IGF Hormonal Network in Endometrial Cancer: Functions, Regulation, and Targeting Approaches. Front Endocrinol (Lausanne) 2014; 5:76. [PMID: 24904527 PMCID: PMC4032924 DOI: 10.3389/fendo.2014.00076] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2014] [Accepted: 05/02/2014] [Indexed: 12/29/2022] Open
Abstract
Epidemiological as well as clinical and experimental data identified the insulin-like growth factors (IGF1, IGF2) as important players in gynecological cancers in general, and endometrial tumors in particular. The IGF1 receptor (IGF1R), which mediates the proliferative and anti-apoptotic activities of both ligands, emerged in recent years as a promising therapeutic target in oncology. However, most clinical trials conducted so far led to mixed results, emphasizing the need to identify biomarkers that can predict responsiveness to anti-IGF1R-targeted therapies. This article will review recent data regarding the role and expression of IGF system components in endometrial cancer. In addition, we will review data on the interplay between the IGF signaling pathway and tumor suppressors p53 and breast cancer susceptibility gene-1 (BRCA1). Anti-oncogenes p53 and BRCA1 play a key role in the etiology of gynecological cancers and, therefore, their interaction with IGF1R is of high relevance in translational terms. A better understanding of the complex mechanisms underlying the regulation of the IGF system will improve our ability to develop effective treatment modalities for endometrial tumors.
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Affiliation(s)
- Ilan Bruchim
- Gynecologic Oncology Unit, Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Sava, Israel
| | - Rive Sarfstein
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Haim Werner
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- *Correspondence: Haim Werner, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel e-mail:
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