TY - JOUR
T1 - SIRT1 contributes in part to cisplatin resistance in cancer cells by altering mitochondrial metabolism
AU - Liang, Xing Jie
AU - Finkel, Toren
AU - Shen, Ding Wu
AU - Yin, Jun Jie
AU - Aszalos, Adorjan
AU - Gottesman, Michael M.
PY - 2008/9/1
Y1 - 2008/9/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-07-2130
DO - 10.1158/1541-7786.MCR-07-2130
M3 - Article
C2 - 18723829
AN - SCOPUS:53349091778
SN - 1541-7786
VL - 6
SP - 1499
EP - 1506
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 9
ER -