SIRT1 contributes in part to cisplatin resistance in cancer cells by altering mitochondrial metabolism.
SIRT1 contributes in part to cisplatin resistance in cancer cells by altering mitochondrial metabolism.
复制标题
DOI：
10.1158/1541-7786.mcr-07-2130
复制
发表时间：
2008-09
影响因子：
5.2
通讯作者：
Gottesman, Michael M.
中科院分区：
文献类型：
--
作者：
Liang, Xing-Jie;Finkel, Toren;Shen, Ding-Wu;Yin, Jun-Jie;Aszalos, Adorjan;Gottesman, Michael M.
肿瘤经常对顺铂产生耐药性，顺铂是一种铂类药物，用作当今化疗方案的基石，显著降低了其在临床中的有用性。尽管已知顺铂耐药（CP-r）癌细胞通常生长较慢，并且对包括营养素在内的各种化合物的摄取减少，但肿瘤代谢对顺铂耐药的影响尚不清楚。发现在CP-r细胞中，与顺铂敏感（CP-s）亲本癌细胞相比，由于线粒体的功能障碍和改变的形态，2-脱氧葡萄糖的摄取减少。CP-r细胞过度表达SIRT 1，这是一种在DNA损伤反应和转录沉默中起核心作用的组蛋白脱乙酰酶。在低葡萄糖培养基中孵育药物敏感细胞诱导SIRT 1的表达，并增加细胞对顺铂的耐药性。通过SIRT 1 SMART siRNA双链体减少SIRT 1表达，使>20倍耐药的CP-r细胞对顺铂治疗敏感1.5至2倍，通过SIRT 1 cDNA转染的SIRT 1过表达使CP-s细胞中的顺铂耐药性增加2至3倍。因此，我们的研究结果表明，SIRT 1介导的葡萄糖使用减少和线粒体代谢改变是导致细胞对顺铂耐药的几种改变之一。
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 to cisplatin-sensitive (CP-s) 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 siRNA 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 CP-s 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.