title: Combining p53 stabilizers with metformin induces synergistic apoptosis through regulation of energy metabolism in castration-resistant prostate cancer.
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.
authors.affiliation: a Department of Biochemistry , Purdue University , West Lafayette , IN , USA.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.affiliation: b Department of Dermatology , University of Wisconsin , Madison , WI , USA.
authors.forename: Nihal
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: a Department of Biochemistry , Purdue University , West Lafayette , IN , USA.|c Center for Cancer Research, Purdue University , West Lafayette , IN , USA.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D000083:Acetanilides; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D056564:Sirtuin 1; D013890:Thiourea; D016159:Tumor Suppressor Protein p53; D000097869:Polo-Like Kinase 1; C518477:BI 2536; C000594735:tenovin-1; C447939:SIRT1 protein, human
keywords: BI2536; Plk1; SIRT1; Tenovin-1; glycolysis; metformin; oxidative phosphorylation; p53