Metformin induces degradation of cyclin D1 via AMPK/GSK3β axis in ovarian cancer

Hye Ran Gwak, Youngmin Kim, Haein An, Danny N. Dhanasekaran, Yong-Sang Song

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)349-358
Number of pages10
JournalMolecular Carcinogenesis
Volume56
Issue number2
DOIs
StatePublished - 1 Feb 2017

Fingerprint

AMP-Activated Protein Kinases
Metformin
Cyclin D1
Ovarian Neoplasms
Proteasome Endopeptidase Complex
Ubiquitin
Neoplasms
70-kDa Ribosomal Protein S6 Kinases
G1 Phase Cell Cycle Checkpoints
Cultured Cells
Phosphorylation
Morbidity
Mortality

Keywords

  • AMPK
  • GSK3β
  • cyclin D1
  • metformin
  • ovarian cancer

Cite this

Gwak, Hye Ran ; Kim, Youngmin ; An, Haein ; Dhanasekaran, Danny N. ; Song, Yong-Sang. / Metformin induces degradation of cyclin D1 via AMPK/GSK3β axis in ovarian cancer. In: Molecular Carcinogenesis. 2017 ; Vol. 56, No. 2. pp. 349-358.
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Metformin induces degradation of cyclin D1 via AMPK/GSK3β axis in ovarian cancer. / Gwak, Hye Ran; Kim, Youngmin; An, Haein; Dhanasekaran, Danny N.; Song, Yong-Sang.

In: Molecular Carcinogenesis, Vol. 56, No. 2, 01.02.2017, p. 349-358.

Research output: Contribution to journalArticle

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