Abstract 504: Identification of RSK2 as a novel regulator of the ER stress-activated autophagy in cancer cells
Authors: Cheng Yan , Ren Xingcong , Zhang Li , Yang Jin-ming 
Published: May 2015

Abstract
Endoplasmic reticulum (ER) is an organelle that plays an essential role in protein folding and post-translational modification, but is often stressed by various physiological and pathological stimuli. To recover normal ER function, an evolutionarily conserved response, termed unfolded protein response (UPR), is triggered. Recently, it has been reported that autophagy, a cellular self-degradative process, is also activated in response to ER stress for removal of the unfolded proteins that cannot be eliminated via the ubiquitin/proteasome system. Although the importance of autophagy in mitigating ER stress has been increasingly appreciated, the molecular mechanisms and pathways by which ER stress induces autophagy remain incompletely understood. Here, we report that p90 ribosomal S6 kinase 2 (RSK2), a serine/threonine protein kinase implicated in control of cell growth and differentiation, plays a critical role in regulating the ER stress-induced autophagy. In the human breast cancer cell lines, MCF-7 and MDA-MB-231, we observed a concomitant activation of autophagy and RSK2 following treatment with the ER stressors, tunicamycin and thapsigargin. Notably, silencing of RSK2 expression blunted the autophagic response in the ER stressed cells. To explore the pathway linking RSK2 activation and ER stress, we determined the role of IRE1α, an ER membrane-associated protein that mediates UPR and alleviates ER stress. We demonstrated in the ER stressed cells that silencing of IRE1α expression blocked the phosphorylation of RSK2, and that partial inhibition of UPR by suppressing eIF2α led to increases in the protein levels of IRE1α and phospho-RSK2, suggesting that IRE1α is required for activation of RSK2 under ER stress. AMP-activated protein kinase (AMPK), an energy sensor that regulates cellular metabolism and a positive regulator of autophagy, appeared to play a role in the RSK2-activated autophagy, as silencing of RSK2 expression caused a reduction in the level of phospho-AMPK. Furthermore, suppression of the ER stress-activated autophagy via silencing of RSK2 expression aggravated ER stress and promoted apoptotic cell death in the cancer cells. This study identified RSK2 as a critical regulator of autophagy under ER stress, and demonstrated the involvement of the IRE1α-RSK2-AMPK pathway in this process. As ER stress is highly induced in a variety of cancers and is closely associated with oncogenesis, cancer cell survival, and resistance to anti-cancer therapies, the revelation of the role of RSK2 in ER stress-induced autophagy provides an additional rationale for targeting RSK2 as a potential therapeutic strategy in cancer treatment.
Citation Format: Yan Cheng, Xingcong Ren, Li Zhang, Jin-ming Yang. Identification of RSK2 as a novel regulator of the ER stress-activated autophagy in cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 504. doi:10.1158/1538-7445.AM2014-504