Abstract
Clusterin (CLU) is a stress-activated chaperone, which plays an important role in cancer development and progression through promoting cell survival. However, the exact mechanism of how CLU exerts its cell protective role under ER stress condition is still unclear. Therefore, in order to explore the molecular mechanisms by which CLU inhibited ER stress-induced apoptosis, HCC cell lines were treated with tunicamycin (TN), an ER stress inducer. We found that the expressions of both CLU and GRP78 were increased after TN treatment. Knockdown of CLU expression in SMMC7721 and HCCLM3 cells inhibited GRP78 expression after TN treatment and enhanced ER stress-induced apoptosis, whereas over-expression of CLU in HepG2 cells increased GRP78 expression after TN induction and abolished the effect of TN on cell apoptosis. Furthermore, knockdown of GRP78 expression in CLU-HepG2 cells abrogated the protective role of CLU under ER stress condition. Co-immunoprecipitation (co-IP) and confocal microscopy experiments confirmed the direct interaction between CLU and GRP78 under ER stress condition. The effect of CLU knockdown on GRP78 expression and cell apoptosis in HCC tumors were further determined in orthotopic xenograft tumor model. Knockdown of CLU expression in HCCLM3 cells inhibited GRP78 expression in tumor tissues, accompanied with increased number of apoptotic cancer cells. Moreover, the correlation between CLU and GRP78 expression was further determined in clinical HCC specimens. Taken together, these findings reveal that CLU protects HCC cells from ER stress induced apoptosis at least partially through interacting with GRP78.
Highlights
The endoplasmic reticulum (ER) is an essential site of cellular homeostasis regulation, especially for the unfolded protein response (UPR)
Shuda et al demonstrated that Glucose-regulated protein 78 (GRP78) mRNA was elevated in hepatocellular carcinoma (HCC) tissues compared to normal liver tissues, which indicated a possible involvement of the ER stress pathway in hepatocarcinogenesis [6]
It has been reported that GRP78 could mediated the efficacy of several anticancer agents including sorafenib [7], gemcitabine [8] and curcumin [9], which may contribute to the treatment failure in HCC
Summary
The endoplasmic reticulum (ER) is an essential site of cellular homeostasis regulation, especially for the unfolded protein response (UPR). Accumulating evidence indicated that Glucose-regulated protein 78 (GRP78), a central regulator of UPR, played a critical role in cellular adaptation and survival under stress conditions. Shuda et al demonstrated that GRP78 mRNA was elevated in HCC tissues compared to normal liver tissues, which indicated a possible involvement of the ER stress pathway in hepatocarcinogenesis [6]. It has been reported that GRP78 could mediated the efficacy of several anticancer agents including sorafenib [7], gemcitabine [8] and curcumin [9], which may contribute to the treatment failure in HCC. Given the critical role of GRP78 in cytoprotection and anticancer treatment resistance, further study of the regulatory mechanism for GRP78 will provide novel insights in HCC therapeutics
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