Combining p53 stabilizers with metformin induces synergistic apoptosis through regulation of energy metabolism in castration-resistant prostate cancer

Long Chen, Nihal Ahmad, Xiaoqi Liu

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Since altered energy metabolism is a hallmark of cancer, many drugs targeting metabolic pathways are in active clinical trials. The tumor suppressor p53 is often inactivated in cancer, either through downregulation of protein or loss-of-function mutations. As such, stabilization of p53 is considered as one promising approach to treat those cancers carrying wild type (WT) p53. Herein, SIRT1 inhibitor Tenovin-1 and polo-like kinase 1 (Plk1) inhibitor BI2536 were used to stabilize p53. We found that both Tennovin-1 and BI2536 increased the anti-neoplastic activity of metformin, an inhibitor of oxidative phosphorylation, in a p53 dependent manner. Since p53 has also been shown to regulate metabolic pathways, we further analyzed glycolysis and oxidative phosphorylation upon drug treatments. We showed that both Tennovin-1 and BI2536 rescued metformin-induced glycolysis and that both Tennovin-1 and BI2536 potentiated metformin-associated inhibition of oxidative phosphorylation. Of significance, castration-resistant prostate cancer (CRPC) C4-2 cells show a much more robust response to the combination treatment than the parental androgen-dependent prostate cancer LNCaP cells, indicating that targeting energy metabolism with metformin plus p53 stabilizers might be a valid approach to treat CRPC carrying WT p53.

Original languageEnglish
Pages (from-to)840-849
Number of pages10
JournalCell Cycle
Volume15
Issue number6
DOIs
StatePublished - Mar 18 2016

Bibliographical note

Funding Information:
L Chen was financially supported by China Scholarship Council (CSC). This work was supported by NIH grants R01 CA157429 (XL), R01 AR059130 (NA), R01 CA176748 (NA) and ACS grant RSG-13-073 (XL).

Publisher Copyright:
© 2016 Taylor & Francis.

Keywords

  • BI2536
  • Plk1
  • SIRT1
  • Tenovin-1
  • glycolysis
  • metformin
  • oxidative phosphorylation
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Combining p53 stabilizers with metformin induces synergistic apoptosis through regulation of energy metabolism in castration-resistant prostate cancer'. Together they form a unique fingerprint.

Cite this