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RACK 1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE 1 / XBP 1 axis

Sorafenib is one of the preferred drugs for the treatment of advanced primary hepatocellular carcinoma (HCC). However, its side-effects and acquired resistance limit its use. The unfolded protein response (UPR) induced by chemotherapeutics has been demonstrated to be required for tumor cells to maintain malignancy and therapy resistance. Activation of the IRE1/XBP1 pathway during the UPR is important for tumor survival under pathophysiological conditions. In the present study, we found that the UPR was activated and RACK1 was overexpressed in three human HCC cell lines and in HCC samples. Activation of the IRE1/XBP1 signaling pathway plays a protective role when HCC cells encounter endoplasmic reticulum (ER) stress due to in vitro sorafenib treatment. We then found that the interaction between IRE1 and RACK1 was essential for the activation of IRE1 signaling in sorafenibtreated cells. Exogenous overexpression of RACK1 enhanced the phosphorylation level of IRE1 and increased XBP1 mRNA splicing activity, which protected the HCC cells from sorafenib-induced apoptosis. However, the re-expression of RACK1 led HCC cells to regain susceptibility to sorafenibinduced apoptosis. Taken together, the present study suggests that the RACK1/IRE1 complex may contribute to activation of the UPR in HCC cells. Targeting RACK1 in combination with sorafenib administration is a potential strategy for clinical trials of advanced HCC treatment. Introduction Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and a common cause of cancerrelated death globally (1). Unfortunately, the prognosis, early diagnosis and treatment of HCC remain poor. Few patients diagnosed with HCC are eligible for curative therapies, including surgical resection, percutaneous ablation and liver transplantation. Most patients are diagnosed at a late stage of the disease when potentially curative therapies are least effective (2,3). Therefore, new therapies are urgently needed for these patients. Sorafenib, an oral multikinase inhibitor of several tyrosine protein kinases and Raf kinases, induces apoptosis in human leukemia and other malignant cells, and is currently the only drug categorized as a preferred treatment for advanced primary HCC (4,5). Investigators have reported that sorafenib inhibits tumor cell proliferation and promotes apoptosis by inhibiting several kinases in the mitogen-activated protein kinase (MAPK) pathway and the translation of pro-survival factors, such as Mcl-1 and Bcl-2 (6-8). Clinical studies have confirmed the efficacy of sorafenib during HCC treatment; however, the drug has several side-effects, and resistance to sorafenib is increasing. Therefore, it is necessary to clarify the mechanisms of sorafenib chemoresistance and to identify other therapeutic biomarkers that might be combined with sorafenib to improve its efficacy. Cancer cells commonly encounter endoplasmic reticulum (ER) stress during tumor initiation and progression due to hypoxia, glucose deprivation, DNA damage or ER calcium depletion (9). The unfolded protein response (UPR) activated during ER stress is a compensatory cellular defense mechanism and an adaptive response that allows tumor cells to survive under these pathophysiological conditions (10). The UPR in response to chemotherapeutics is necessary for tumor cells to maintain malignancy and therapy resistance (11). Identification of the UPR components that are activated or suppressed in tumors and investigation of the potential of cancer therapeutics by targeting the UPR may be potentially useful to inhibit tumor growth and improve cancer therapy (12,13). IRE1 is the only identified ER stress sensor in yeast and is essential for the UPR in animals and plants (14). As an ER transmembrane protein, IRE1 monitors ER homeostasis through an ER RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis TI ZHOU1, XING Lv1, XIN GUO1, BAI RUAN1, DONG LIU1, RUI DING1, YUAN GAO1, JIE DING2, KEFENG DOU1 and YONG CHEN1 1Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032; 2Department of Pharmacy, Xi'an Central Hospital, Xi'an, Shaanxi 710032, P.R. China Received December 27, 2014; Accepted March 24, 2015 DOI: 10.3892/or.2015.3920 Correspondence to: Professor Yong Chen or Professor Kefeng Dou, Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China E-mail: yongchen1962@gmail.com E-mail: doukf_fmmu@foxmail.com Abbreviations: HCC, hepatocellular carcinoma; ER, endoplasmic reticulum; UPR, unfolded protein response; XBP-1, X-box binding protein 1; TM, tunicamycin; ERAD, ER associated degradation; GRP78, 78-kDa glucose-regulated protein; IRE1, inositol-requiring enzyme 1; RACK1, receptor for activated C kinase 1