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.
Keywords:
BI2536; Plk1; SIRT1; Tenovin-1; glycolysis; metformin; oxidative phosphorylation; p53.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetanilides / pharmacology*
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Drug Synergism
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Drug Therapy, Combination
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Gene Expression Regulation, Neoplastic*
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Glycolysis / drug effects
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Humans
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Male
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Metformin / pharmacology*
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mitosis / drug effects
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Oxidative Phosphorylation / drug effects
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Polo-Like Kinase 1
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Prostate / drug effects
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Prostate / metabolism
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Prostate / pathology
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Prostatic Neoplasms, Castration-Resistant / drug therapy
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Prostatic Neoplasms, Castration-Resistant / genetics
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Prostatic Neoplasms, Castration-Resistant / metabolism
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Prostatic Neoplasms, Castration-Resistant / pathology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Pteridines / pharmacology*
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Signal Transduction
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Sirtuin 1 / antagonists & inhibitors
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Sirtuin 1 / genetics
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Sirtuin 1 / metabolism
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Thiourea / analogs & derivatives*
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Thiourea / pharmacology
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Tumor Suppressor Protein p53 / agonists*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Acetanilides
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Antineoplastic Agents
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BI 2536
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Cell Cycle Proteins
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Proto-Oncogene Proteins
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Pteridines
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Tumor Suppressor Protein p53
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Metformin
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tenovin-1
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Protein Serine-Threonine Kinases
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SIRT1 protein, human
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Sirtuin 1
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Thiourea