Sirtuins have emerged as a promising novel class of anti-cancer drug targets. Inhibition of SIRT1 and SIRT2 induces apoptosis in cancer cells and they play multifaceted roles in regulating autophagy. In the present study, we found that salermide, a SIRT1/2-specific inhibitor or small interfering RNAs (siRNAs) to block SIRT1/2 expression could induce autophagy in human NSCLC cells. Moreover, SIRT1/2 inhibition increased the expression levels of ATF4 and DDIT4 and downregulated p-RPS6KB1 and p-EIF4EBP1, two downstream molecules of mTORC1. Moreover, ATF4 or DDIT4 knockdown attenuated salermide-induced autophagy, suggesting that SIRT1/2 inhibition induced autophagy through the ATF4-DDIT4-mTORC1 axis. Mechanistically, SIRT1/2 inhibition led to HSPA5 acetylation and dissociation from EIF2AK3, leading to ER stress response and followed by upregulation of ATF4 and DDIT4, triggering autophagy. Silencing of the autophagic gene ATG5 in lung cancer cells resulted in increased apoptotic cell death induced by SIRT1/2 inhibition. Our data show that inhibition of SIRT1/2 induces pro-survival autophagy via acetylation of HSPA5 and subsequent activation of ATF4 and DDIT4 to inhibit the mTOR signaling pathway in NSCLC cells. These findings suggest that combinatorial treatment with SIRT1/2 inhibitors and pharmacological autophagy inhibitors is an effective therapeutic strategy for cancer therapy.

中文翻译：

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SIRT1 / 2的抑制通过人类肺癌细胞中的ATF4-DDIT4-mTORC1轴上调HSPA5乙酰化并诱导生存前自噬。

Sirtuins已经成为一种有前途的新型抗癌药物靶标。抑制SIRT1和SIRT2诱导癌细胞凋亡，它们在调节自噬中发挥多方面的作用。在本研究中，我们发现沙雷特胺，一种SIRT1 / 2特异性抑制剂或小干扰RNA（siRNA）可以阻断SIRT1 / 2的表达，从而诱导人NSCLC细胞自噬。此外，SIRT1 / 2抑制增加了ATF4和DDIT4的表达水平，并下调了mTORC1的两个下游分子p-RPS6KB1和p-EIF4EBP1。此外，ATF4或DDIT4组合体减弱了杀虫灵诱导的自噬，提示SIRT1 / 2抑制通过ATF4-DDIT4-mTORC1轴诱导自噬。从机理上讲，SIRT1 / 2抑制作用导致HSPA5乙酰化并从EIF2AK3解离，导致ER应激反应，然后ATF4和DDIT4上调，触发自噬。肺癌细胞中自噬基因ATG5的沉默导致SIRT1 / 2抑制诱导的凋亡细胞死亡增加。我们的数据表明，SIRT1 / 2的抑制通过HSPA5的乙酰化以及随后的ATF4和DDIT4的激活来诱导NSCLC细胞中的mTOR信号通路，从而诱导生存前自噬。这些发现表明，SIRT1 / 2抑制剂和药理自噬抑制剂的组合治疗是癌症治疗的有效治疗策略。我们的数据表明，SIRT1 / 2的抑制通过HSPA5的乙酰化以及随后的ATF4和DDIT4的激活来诱导NSCLC细胞中的mTOR信号通路，从而诱导生存前自噬。这些发现表明，SIRT1 / 2抑制剂和药理自噬抑制剂的组合治疗是癌症治疗的有效治疗策略。我们的数据表明，SIRT1 / 2的抑制通过HSPA5的乙酰化以及随后的ATF4和DDIT4的激活来诱导NSCLC细胞中的mTOR信号通路，从而诱导生存前自噬。这些发现表明，SIRT1 / 2抑制剂和药理自噬抑制剂的组合治疗是癌症治疗的有效治疗策略。