RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis

  • Authors:
    • Ti Zhou
    • Xing Lv
    • Xin Guo
    • Bai Ruan
    • Dong Liu
    • Rui Ding
    • Yuan Gao
    • Jie Ding
    • Kefeng Dou
    • Yong Chen
  • View Affiliations

  • Published online on: April 21, 2015     https://doi.org/10.3892/or.2015.3920
  • Pages: 3006-3014
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Abstract

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 sorafenib-treated 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 sorafenib-induced 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.
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June-2015
Volume 33 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Zhou T, Lv X, Guo X, Ruan B, Liu D, Ding R, Gao Y, Ding J, Dou K, Chen Y, Chen Y, et al: RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis. Oncol Rep 33: 3006-3014, 2015.
APA
Zhou, T., Lv, X., Guo, X., Ruan, B., Liu, D., Ding, R. ... Chen, Y. (2015). RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis. Oncology Reports, 33, 3006-3014. https://doi.org/10.3892/or.2015.3920
MLA
Zhou, T., Lv, X., Guo, X., Ruan, B., Liu, D., Ding, R., Gao, Y., Ding, J., Dou, K., Chen, Y."RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis". Oncology Reports 33.6 (2015): 3006-3014.
Chicago
Zhou, T., Lv, X., Guo, X., Ruan, B., Liu, D., Ding, R., Gao, Y., Ding, J., Dou, K., Chen, Y."RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis". Oncology Reports 33, no. 6 (2015): 3006-3014. https://doi.org/10.3892/or.2015.3920