Metformin induces degradation of cyclin D1 via AMPK/GSK3β axis in ovarian cancer
Abstract
Metformin, which is widely used as an anti-diabetic drug, reduces cancer related morbidity and mortality. However, the role of metformin in cancer is not fully understood. Here, we first describe that the anti-cancer effect of metformin is mediated by cyclin D1 deregulation via AMPK/GSK3β axis in ovarian cancer cells. Metformin promoted cytotoxic effects only in the cancer cells irrespective of the p53 status and not in the normal primary-cultured cells. Metformin induced the G1 cell cycle arrest, in parallel with a decrease in the protein expressions of cyclin D1 without affecting its transcriptional levels. Using a proteasomal inhibitor, we could address that metformin-induced decrease in cyclin D1 through the ubiquitin/proteasome process. Cyclin D1 degradation by metformin requires the activation of GSK3β, as determined based on the treatment with GSK3β inhibitors. The activation of GSK3β correlated with the inhibitory phosphorylation by Akt as well as p70S6K through AMPK activation in response to metformin. These findings suggested that the anticancer effects of metformin was induced due to cyclin D1 degradation via AMPK/GSK3β signaling axis that involved the ubiquitin/proteasome pathway specifically in ovarian cancer cells. © 2016 Wiley Periodicals, Inc.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
GSK3β is a target of metformin.
“GSK3 b has been shown previously to be a target of metformin (Gwak et al., 2017).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Gwak et al., 2017
Cites
Hanahan, D., & Weinberg, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)81683-9 · Cited by 29,219 · see citing works
Integrated genomic analyses of ovarian carcinoma
Perou, C. M. (2019) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/hvp3-wg08 · Cited by 7,927 · see citing works
Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B
Cross, D. A. E., Alessi, D. R., Cohen, P., Andjelkovich, M., & Hemmings, B. A. (1995) · Nature · doi:10.1038/378785a0 · Cited by 5,244 · see citing works
Signal integration by JNK and p38 MAPK pathways in cancer development
Wagner, E. F., & Nebreda, Á. R. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2694 · Cited by 2,583 · see citing works
Giovannucci, E., Harlan, D. M., Archer, M. C., Bergenstal, R. M., Gapstur, S. M., Habel, L. A., Pollak, M., Regensteiner, J. G., & Yee, D. (2010) · Diabetes Care · doi:10.2337/dc10-0666 · Cited by 2,366 · see citing works
The LKB1-AMPK pathway: metabolism and growth control in tumour suppression
Shackelford, D. B., & Shaw, R. J. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2676 · Cited by 1,943 · see citing works
Cohen, P., & Frame, S. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35096075 · Cited by 1,478 · see citing works
Cyclin D as a therapeutic target in cancer
Musgrove, E. A., Caldon, C. E., Barraclough, J., Stone, A., & Sutherland, R. L. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3090 · Cited by 1,370 · see citing works
Metformin—mode of action and clinical implications for diabetes and cancer
Pernicova, I., & Korbonits, M. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.256 · Cited by 1,345 · see citing works
New Users of Metformin Are at Low Risk of Incident Cancer
Libby, G., Donnelly, L. A., Donnan, P. T., Alessi, D. R., Morris, A. D., & Evans, J. M. M. (2009) · Diabetes Care · doi:10.2337/dc08-2175 · Cited by 996 · see citing works
Bowker, S. L., Majumdar, S. R., Veugelers, P., & Johnson, J. A. (2006) · Diabetes Care · doi:10.2337/diacare.29.02.06.dc05-1558 · Cited by 933 · see citing works
Sahra, I. B., Laurent, K., Loubat, A., Giorgetti-Peraldi, S., Colosetti, P., Auberger, P., Tanti, J. F., Le Marchand-Brustel, Y., & Bost, F. (2008) · Oncogene · doi:10.1038/sj.onc.1211024 · Cited by 861 · see citing works
Beyond chemotherapy: targeted therapies in ovarian cancer
Yap, T. A., Carden, C. P., & Kaye, S. B. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2583 · Cited by 495 · see citing works
GSK-3β regulates cyclin D1 expression: A new target for chemotherapy
Takahashi‐Yanaga, F., & Sasaguri, T. (2007) · Cellular Signalling · doi:10.1016/j.cellsig.2007.10.018 · Cited by 261 · see citing works
Pierotti, M. A., Berrino, F., Gariboldi, M., Melani, C. C., Mogavero, A., Negri, T., Pasanisi, P., & Pilotti, S. (2012) · Oncogene · doi:10.1038/onc.2012.181 · Cited by 251 · see citing works
Bowen, N. J., Walker, L. D., Matyunina, L. V., Logani, S., Totten, K. A., Benigno, B. B., & McDonald, J. F. (2009) · BMC Medical Genomics · doi:10.1186/1755-8794-2-71 · Cited by 239 · see citing works
Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression
Lee, Y., Dominy, J. E., Choi, Y. J., Jurczak, M., Tolliday, N., Camporez, J. P., Chim, H., Lim, J.-H., Ruan, H.-B., Yang, X., et al. (2014) · Nature · doi:10.1038/nature13267 · Cited by 234 · see citing works
Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK
Liu, X., Chhipa, R. R., Pooya, S., Wortman, M. D., Yachyshin, S., Chow, L. M. L., Kumar, A., Zhou, X., Sun, Y. H., Quinn, B., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311121111 · Cited by 222 · see citing works
Current Management Strategies for Ovarian Cancer
Aletti, G. D., Gallenberg, M. M., Cliby, W. A., Jatoi, A., & Hartmann, L. C. (2007) · Mayo Clinic Proceedings · doi:10.4065/82.6.751 · Cited by 196 · see citing works
Activator or inhibitor? GSK-3 as a new drug target
Takahashi‐Yanaga, F. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.04.022 · Cited by 194 · see citing works
Metformin targets ovarian cancer stem cells in vitro and in vivo
Shank, J., Yang, K., Ghannam, J., et al. (2012) · Gynecologic Oncology · doi:10.1016/j.ygyno.2012.07.115 · Cited by 191 · see citing works
Metformin intake is associated with better survival in ovarian cancer
Kumar, S., Meuter, A., Thapa, P. B., Langstraat, C. L., Giri, S., CHIEN, J. R., Rattan, R., Cliby, W. A., & Shridhar, V. (2012) · Cancer · doi:10.1002/cncr.27706 · Cited by 161 · see citing works
Kurokawa, T., Yoshida, Y., Kawahara, K., et al. (2004) · International Journal of Cancer · doi:10.1002/ijc.20057 · Cited by 156 · see citing works
Bali, A., O’Brien, P. M., Edwards, L. S., Sutherland, R. L., Hacker, N. F., & Henshall, S. M. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-03-0751 · Cited by 148 · see citing works
Gwak, H., Kim, S., Dhanasekaran, D. N., & Song, Y. S. (2015) · Cancer Letters · doi:10.1016/j.canlet.2015.11.032 · Cited by 88 · see citing works
Self-citationDiverse roles of GSK-3: tumor promoter-tumor suppressor, target in cancer therapy.
McCubrey, J., Davis, N. M., Abrams, S., Montalto, G., Cervello, M., Bäsecke, J., Libra, M., Nicoletti, F., Cocco, L., Martelli, A., et al. (2014) · Advances in Biological Regulation · doi:10.1016/j.jbior.2013.09.013 · Cited by 83 · see citing works
Gwak, H., Haegeman, G., Tsang, B. K., & Song, Y. S. (2014) · Molecular Carcinogenesis · doi:10.1002/mc.22227 · Cited by 82 · see citing works
Self-citationAshford, A. L., Oxley, D., Kettle, J. G., Hudson, K., Guichard, S. M., Cook, S. J., & Lochhead, P. A. (2013) · Biochemical Journal · doi:10.1042/bj20130461 · Cited by 81 · see citing works
The LKB1-AMPK Pathway—Friend or Foe in Cancer?
Hardie, D. G. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.01.009 · Cited by 73 · see citing works
Overexpression of cyclin D1 and c-Myc gene products in human primary epithelial ovarian cancer
Chen, C., Shen, J., LEE, W.-J., & CHOW, S.-N. (2005) · International Journal of Gynecological Cancer · doi:10.1111/j.1525-1438.2005.00150.x · Cited by 69 · see citing works
Glucose as a prognostic factor in ovarian carcinoma
Lamkin, D. M., Spitz, D. R., Shahzad, M. M. K., Zimmerman, B. M., Lenihan, D. J., DeGeest, K., Lubaroff, D. M., Shinn, E. H., Sood, A. K., & Lutgendorf, S. K. (2009) · Cancer · doi:10.1002/cncr.24126 · Cited by 65 · see citing works
Moon, H. S., Kim, B., Gwak, H., Suh, D. H., & Song, Y. S. (2015) · Molecular Carcinogenesis · doi:10.1002/mc.22284 · Cited by 61 · see citing works
Self-citationMetabolic approaches to overcoming chemoresistance in ovarian cancer
Suh, D. H., Kim, M., No, J. H., Chung, H. H., & Song, Y. S. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2011.06095.x · Cited by 50 · see citing works
Self-citationCai, G., Wang, J., Xin, X., et al. (2007) · International Journal of Oncology · doi:10.3892/ijo.31.3.657 · Cited by 49 · see citing works
Xie, Y., PENG, Z., SHI, M., et al. (2014) · Molecular Medicine Reports · doi:10.3892/mmr.2014.2490 · Cited by 47 · see citing works
Kim, T. H., Suh, D. H., Kim, M., & Song, Y. S. (2014) · BioMed Research International · doi:10.1155/2014/132702 · Cited by 44 · see citing works
Self-citationCyclin D1 predicts the prognosis of advanced serous ovarian cancer
Hashimoto, T., Yanaihara, N., Okamoto, A., Nikaido, T., Saito, M., Takakura, S., YASUDA, M., Sasaki, H., Ochiai, K., & Tanaka, T. (2011) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2011.194 · Cited by 43 · see citing works
Epidemiological characteristics of ovarian cancer in Korea
Park, B., Park, S., Park, S., et al. (2010) · Journal of Gynecologic Oncology · doi:10.3802/jgo.2010.21.4.241 · Cited by 40 · see citing works
Fu, Y., Hu, D., Qiu, J. G., et al. (2011) · International Journal of Gynecological Cancer · doi:10.1097/igc.0b013e31820d7366 · Cited by 39 · see citing works
Zhao, B. Q., & Li, X. (2014) · Oncology Reports · doi:10.3892/or.2014.3126 · Cited by 22 · see citing works
Cyclin D1 overexpression in esophageal cancer from southern China and its clinical significance
Huang, X., Tie-hua, R., Peng, L., et al. (2005) · Cancer Letters · doi:10.1016/j.canlet.2005.01.040 · Cited by 20 · see citing works
Yao, X.-M., Ye, S., XIAO, C.-C., Gu, J., Yang, D., & Wang, S. (2012) · Molecular Medicine Reports · doi:10.3892/mmr.2015.3446 · Cited by 15 · see citing works
GSK-3β as a driving force in ovarian cancer
Li, D. (2006) · Cell Research · doi:10.1038/sj.cr.7310082 · Cited by 5 · see citing works
Simonelli, C., Bertolotti, M., Sabbatini, P. J., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2013.31.15_suppl.5522 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Elgendy, M., Cirò, M., Hosseini, A., Weiszmann, J., Mazzarella, L., Ferrari, E., Cazzoli, R., Curigliano, G., DeCensi, A., Bonanni, B., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.03.007 · Cited by 299 · see citing works
- Authors
- Gwak, H., Kim, Y., An, H., Dhanasekaran, D. N., & Song, Y. S.
- Affiliations
- Seoul National University (KR)
- OU Health Stephenson Cancer Center (US)
- Corresponding author
- Song, Yong Sang
- Venue
- Molecular Carcinogenesis
- Publisher
- Wiley
- Published
- 2016-04-29
- Volume
- 56
- Issue
- 2
- Pages
- 349-358
- ISSN
- 0899-1987 (ISSN-L)
- 1098-2744
- OpenAlex
- W2359972779
- Cited by
- 53
- References
- 44
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 6 · 2022: 6 · 2021: 6 · 2020: 5 · 2019: 7 · 2018: 10 · 2017: 8 · 2016: 1
- FWCI
- 4.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Carcinogenesis (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA116984)
- National Research Foundation of Korea
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- metformin, cyclin D1, ovarian cancer, AMPK, GSK3β, ubiquitin-proteasome system, protein degradation, G1 cell cycle arrest, Akt phosphorylation, p70S6K, anticancer drug repurposing
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Antineoplastic Agents, Female, Humans, Hypoglycemic Agents, Metformin, Ovarian Neoplasms, Ovary, Signal Transduction, Cyclin D1, Cell Line, Tumor, Cell Proliferation, AMP-Activated Protein Kinases, Cell Cycle Checkpoints, Proteolysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
