Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy.
Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy.
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DOI：
10.1158/1535-7163.mct-08-1169
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发表时间：
2009-07
影响因子：
5.7
通讯作者：
Yin XM
中科院分区：
文献类型：
--
作者：
Ding WX;Ni HM;Gao W;Chen X;Kang JH;Stolz DB;Liu J;Yin XM
蛋白酶体和自噬系统是两种进化上保守的降解细胞内物质的机制。它们在功能上是偶联的，蛋白酶体的抑制促进自噬。虽然蛋白酶体的抑制导致细胞死亡，但自噬的抑制可以是促死亡或促存活。为了理解这种二分法的基本机制及其潜在的临床意义，我们用蛋白酶体抑制剂处理了各种转化和非转化的人类细胞。我们发现，在这种情况下，自噬是否起到促生存作用取决于细胞的致癌状态。因此，在转化细胞中，自噬抑制增强了蛋白酶体抑制剂诱导的凋亡，但在非转化细胞中没有。致癌性转化增强了细胞响应压力而启动自噬的能力，反映了转化细胞对自噬的生存依赖性更强。事实上，在异种移植模型中，联合使用硼替佐米（FDA批准的唯一用于临床的蛋白酶体抑制剂）和氯喹（通过干扰溶酶体功能抑制自噬）比单独使用任一种药物更显著地抑制肿瘤生长。这些发现表明，抑制两种细胞内降解系统可能构成以肿瘤特异性方式增强癌症控制的新策略。
The proteasome and the autophagy systems are two evolutionarily conserved mechanisms for degrading intracellular materials. They are functionally coupled and suppression of the proteasome promotes autophagy. While suppression of the proteasome leads to cell death, suppression of autophagy can be either pro-death or pro-survival. To understand the underlining mechanism of this dichotomy and its potential clinical implications, we treated various transformed and non-transformed human cells with proteasome inhibitors. We found that whether autophagy served a pro-survival role in this scenario was contingent on the cellular oncogenic status. Thus autophagy suppression enhanced apoptosis induced by proteasome inhibitors in transformed cells, but not in non-transformed cells. Oncogenic transformation enhanced the ability of cells to initiate autophagy in response to stress, reflecting a stronger dependence of transformed cells on autophagy for survival. Indeed, a combined use of Bortezomib, the only FDA-approved proteasome inhibitor for clinical use, and chloroquine, which inhibits autophagy by disturbing lysosomal functions, suppressed tumor growth more significantly than either agent alone in a xenograft model. These findings indicate that suppression of both intracellular degradation systems could constitute a novel strategy for enhanced cancer control in a tumor-specific way.