title: SIRT1 contributes in part to cisplatin resistance in cancer cells by altering mitochondrial metabolism.
abstract: Tumors frequently develop resistance to cisplatin, a platinum drug used as a cornerstone of present-day chemotherapy regimens, significantly decreasing its usefulness in the clinic. Although it is known that cisplatin-resistant (CP-r) cancer cells commonly grow more slowly and exhibit reduced uptake of various compounds, including nutrients, the effect of tumor metabolism on cisplatin resistance is unclear. It was found that in CP-r cells, uptake of 2-deoxyglucose was reduced due to dysfunction and altered morphology of mitochondria compared with cisplatin-sensitive parental cancer cells. The CP-r cells overexpressed SIRT1, a histone deacetylase that plays a central role in DNA damage response and transcriptional silencing. Incubation of drug-sensitive cells in low glucose medium induced the expression of SIRT1 and increased cellular resistance to cisplatin. Reduced SIRT1 expression by a SIRT1 SMART small interfering RNA duplex sensitized the >20-fold resistant CP-r cells to cisplatin treatment 1.5- to 2-fold, and SIRT1 overexpression by SIRT1 cDNA transfection increased cisplatin resistance in cisplatin-sensitive cells by 2- to 3-fold. Our findings therefore suggest that reduced glucose use and altered mitochondrial metabolism mediated by SIRT1 is one of several alterations that contribute to cellular resistance to cisplatin.
authors: Laboratory of Cell Biology, National Cancer Institute, NIH, Bethesda, MD 20892, USA. liangxj@nanoctr.cn
authors: Xing-Jie
authors: XJ
authors: Liang
authors: Toren
authors: T
authors: Finkel
authors: Ding-Wu
authors: DW
authors: Shen
authors: Jun-Jie
authors: JJ
authors: Yin
authors: Adorjan
authors: A
authors: Aszalos
authors: Michael M
authors: MM
authors: Gottesman
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D022082:Cellular Structures / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003847:Deoxyglucose / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004578:Electron Spin Resonance Spectroscopy; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D010101:Oxygen Consumption; D034741:RNA, Small Interfering / Q000494:pharmacology; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D003847:Deoxyglucose; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D002945:Cisplatin