Synthetic Lethal Metabolic Targeting of Androgen-Deprived Prostate Cancer Cells with Metformin.

Abstract

The initiation of androgen-deprivation therapy (ADT) induces susceptibilities in prostate cancer cells that make them vulnerable to synergistic treatment and enhanced cell death. Senescence results in cell-cycle arrest, but cells remain viable. In this study, we investigated the mechanisms by which prostate cancer cells undergo senescence in response to ADT, and determined whether an FDA-approved antidiabetic drug metformin has a synergistic effect with ADT in prostate cancer both in vitro and in vivo Our results show that longer term exposure to ADT induced senescence associated with p16INK4a and/or p27kip2 induction. The activation of PI3K/AKT and inactivation of AMPK in senescent cells resulted in mTORC1 activation. In addition, the antiapoptotic protein XIAP expression was increased in response to ADT. The addition of metformin following ADT induced apoptosis, attenuated mTOR activation, reduced senescent cell number in vitro, and inhibited tumor growth in prostate cancer patient-derived xenograft models. This study suggests that combining ADT and metformin may be a feasible therapeutic approach to remove persistent prostate cancer cells after ADT.

• Authors: Bing Yang, Shivashankar Damodaran, Tariq A Khemees, Mikolaj J Filon, Adam Schultz, Joseph Gawdzik, Tyler Etheridge, Dmitry Malin, Kyle A Richards, Vincent L Cryns, David F Jarrard
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 19 Issue 11 Pg. 2278-2287 (11 2020) ISSN: 1538-8514 [Electronic] United States
• PMID: 32943543 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Androgens
• Metformin
• Proto-Oncogene Proteins c-akt
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Androgens (metabolism)
• Animals
• Cell Line, Tumor
• Cellular Senescence (genetics)
• Disease Models, Animal
• Energy Metabolism (drug effects)
• Humans
• Male
• Metformin (pharmacology)
• Mice
• Models, Biological
• Phosphatidylinositol 3-Kinases (metabolism)
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Synthetic Lethal Mutations
• Xenograft Model Antitumor Assays