Department of Pharmacy, The Second Xiangya Hospital, Central South University, 410011, Changsha, China.
Xiangya School of Pharmaceutical Sciences, Central South University, 410008, Changsha, China.
Oncogene. 2020 Oct;39(43):6704-6718. doi: 10.1038/s41388-020-01447-0. Epub 2020 Sep 21.
Autophagy can protect stressed cancer cell by degradation of damaged proteins and organelles. However, the regulatory mechanisms behind this cellular process remain incompletely understood. Here, we demonstrate that RSK2 (p90 ribosomal S6 kinase 2) plays a critical role in ER stress-induced autophagy in breast cancer cells. We demonstrated that the promotive effect of RSK2 on autophagy resulted from directly binding of AMPKα2 in nucleus and phosphorylating it at Thr172 residue. IRE1α, an ER membrane-associated protein mediating unfolded protein response (UPR), is required for transducing the signal for activation of ERK1/2-RSK2 under ER stress. Suppression of autophagy by knockdown of RSK2 enhanced the sensitivity of breast cancer cells to ER stress both in vitro and in vivo. Furthermore, we demonstrated that inhibition of RSK2-mediated autophagy rendered breast cancer cells more sensitive to paclitaxel, a chemotherapeutic agent that induces ER stress-mediated cell death. This study identifies RSK2 as a novel controller of autophagy in tumor cells and suggests that targeting RSK2 can be exploited as an approach to reinforce the efficacy of ER stress-inducing agents against cancer.
自噬可以通过降解受损的蛋白质和细胞器来保护应激状态下的癌细胞。然而，这一细胞过程背后的调节机制仍不完全清楚。在这里，我们证明了 RSK2（p90 核糖体 S6 激酶 2）在乳腺癌细胞内质网应激诱导的自噬中起着关键作用。我们证明，RSK2 对自噬的促进作用源于在核内直接结合 AMPKα2 并使其在 Thr172 残基磷酸化。IRE1α 是一种内质网膜相关蛋白，介导未折叠蛋白反应 (UPR)，是在 ER 应激下转导 ERK1/2-RSK2 激活信号所必需的。RSK2 敲低抑制自噬，可增强乳腺癌细胞在体外和体内对 ER 应激的敏感性。此外，我们证明抑制 RSK2 介导的自噬可使乳腺癌细胞对紫杉醇（一种诱导 ER 应激介导的细胞死亡的化疗药物）更敏感。这项研究确定了 RSK2 是肿瘤细胞中自噬的一种新型控制器，并表明靶向 RSK2 可以作为一种增强内质网应激诱导剂对抗癌症的疗效的方法。
