Sensitization of multidrug-resistant human cancer cells to Hsp90 inhibitors by down-regulation of SIRT1.
Sensitization of multidrug-resistant human cancer cells to Hsp90 inhibitors by down-regulation of SIRT1.
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DOI：
10.18632/oncotarget.5343
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发表时间：
2015-11-03
期刊：
影响因子：
--
通讯作者：
Kim SH
中科院分区：
文献类型：
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作者：
Kim HB;Lee SH;Um JH;Oh WK;Kim DW;Kang CD;Kim SH
Hsp 90抑制剂作为抗癌剂的有效性在多药耐药（MDR）的人癌细胞中是有限的，这是由于诱导热休克蛋白（Hsps）如Hsp 70/Hsp 27和P-糖蛋白（P-gp）介导的外排。在本研究中，我们表明，耐药性的Hsp 90抑制剂的MDR人癌细胞可以克服SIRT 1抑制。SIRT 1敲低或SIRT 1抑制剂（苦杏仁素G和EX 527）有效地抑制了人淋巴细胞白血病和人乳腺癌细胞系的几种MDR变体中对Hsp 90抑制剂（17-AAG和AUY 922）的抗性。SIRT 1抑制下调热休克因子1（HSF 1）的表达，随后Hsps和促进Hsp 90多分子伴侣复合物通过Hsp 90/Hsp 70的超乙酰化破坏。这些发现之后是泛素连接酶CHIP介导的突变型p53（mut p53）降解的加速以及随后在SIRT 1抑制后表达P-gp和mut p53的17-AAG处理的MDR癌细胞中P-gp的下调。因此，联合应用Hsp 90抑制剂和SIRT 1抑制剂可能通过下调HSF 1/Hsps、mut p53和P-gp的表达，成为治疗Hsp 90耐药MDR细胞的有效方法。
The effectiveness of Hsp90 inhibitors as anticancer agents was limited in multidrug-resistant (MDR) human cancer cells due to induction of heat shock proteins (Hsps) such as Hsp70/Hsp27 and P-glycoprotein (P-gp)-mediated efflux. In the present study, we showed that resistance to Hsp90 inhibitors of MDR human cancer cells could be overcome with SIRT1 inhibition. SIRT1 knock-down or SIRT1 inhibitors (amurensin G and EX527) effectively suppressed the resistance to Hsp90 inhibitors (17-AAG and AUY922) in several MDR variants of human lymphoblastic leukemia and human breast cancer cell lines. SIRT1 inhibition down-regulated the expression of heat shock factor 1 (HSF1) and subsequently Hsps and facilitated Hsp90 multichaperone complex disruption via hyperacetylation of Hsp90/Hsp70. These findings were followed by acceleration of ubiquitin ligase CHIP-mediated mutant p53 (mut p53) degradation and subsequent down-regulation of P-gp in 17-AAG-treated MDR cancer cells expressing P-gp and mut p53 after inhibition of SIRT1. Therefore, combined treatment with Hsp90 inhibitor and SIRT1 inhibitor could be a more effective therapeutic approach for Hsp90 inhibitor-resistant MDR cells via down-regulation of HSF1/Hsps, mut p53 and P-gp.