Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6561-5. doi: 10.1073/pnas.1204429109. Epub 2012 Apr 9.
Autophagy is a cellular catabolic pathway by which long-lived proteins and damaged organelles are targeted for degradation. Activation of autophagy enhances cellular tolerance to various stresses. Recent studies indicate that a class of anticancer agents, histone deacetylase (HDAC) inhibitors, can induce autophagy. One of the HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA), is currently being used for treating cutaneous T-cell lymphoma and under clinical trials for multiple other cancer types, including glioblastoma. Here, we show that SAHA increases the expression of the autophagic factor LC3, and inhibits the nutrient-sensing kinase mammalian target of rapamycin (mTOR). The inactivation of mTOR results in the dephosphorylation, and thus activation, of the autophagic protein kinase ULK1, which is essential for autophagy activation during SAHA treatment. Furthermore, we show that the inhibition of autophagy by RNAi in glioblastoma cells results in an increase in SAHA-induced apoptosis. Importantly, when apoptosis is pharmacologically blocked, SAHA-induced nonapoptotic cell death can also be potentiated by autophagy inhibition. Overall, our findings indicate that SAHA activates autophagy via inhibiting mTOR and up-regulating LC3 expression; autophagy functions as a prosurvival mechanism to mitigate SAHA-induced apoptotic and nonapoptotic cell death, suggesting that targeting autophagy might improve the therapeutic effects of SAHA.
自噬是一种细胞分解代谢途径，通过该途径，长寿命蛋白和受损的细胞器被靶向降解。自噬的激活增强了细胞对各种应激的耐受性。最近的研究表明，一类抗癌药物，组蛋白去乙酰化酶（HDAC）抑制剂，可以诱导自噬。HDAC 抑制剂之一，琥珀酰亚胺基羟肟酸（SAHA），目前正用于治疗皮肤 T 细胞淋巴瘤，并正在临床试验中用于多种其他癌症类型，包括神经胶质瘤。在这里，我们表明 SAHA 增加了自噬因子 LC3 的表达，并抑制了营养感应激酶哺乳动物雷帕霉素靶蛋白（mTOR）。mTOR 的失活导致自噬蛋白激酶 ULK1 的去磷酸化，从而激活，这对于 SAHA 治疗期间的自噬激活是必不可少的。此外，我们表明在神经胶质瘤细胞中通过 RNAi 抑制自噬会导致 SAHA 诱导的细胞凋亡增加。重要的是，当凋亡被药理学阻断时，自噬抑制也可以增强 SAHA 诱导的非凋亡性细胞死亡。总的来说，我们的研究结果表明，SAHA 通过抑制 mTOR 和上调 LC3 表达来激活自噬；自噬作为一种生存机制，减轻 SAHA 诱导的凋亡和非凋亡性细胞死亡，表明靶向自噬可能改善 SAHA 的治疗效果。
