GRP78 induced by estrogen plays a role in the chemosensitivity of endometrial cancer

ObjectiveMolecular chaperone 78 kDa glucose-regulated protein (GRP78) is a residential protein in the endoplasmic reticulum (ER) that is induced by an unfolded-protein response triggered under many kinds of stress against a cell. GRP78 is also known to act as an anti-apoptotic factor by protecting ER-stress-induced cell death. In this study, we examined the significance of GRP78 expression in endometrial cancer.MethodsTissue samples obtained from patients with a diagnosis of enodometrial cancer were subjected to immunohistochemistry and RT-PCR to determine protein and mRNA expression levels of GRP78 and estrogen receptor α. We used Western blot and RT-PCR to examine whether estrogen induced GRP78 expression in cancer cell lines. Western blots and MTT assays of GRP78 siRNA transfected Ishikawa and HHUA cells were used to demonstrate whether GRP78 is involved in chemoresistence.ResultsGRP78 was highly expressed in well and moderately differentiated endometrial carcinoma. Estrogen induced GRP78 expression, which was correlated with cell viability and resistance to paclitaxel and cisplatin. Western blot analysis indicated that active caspase-3 and the 85-kDa protein poly (ADP-ribose) polymerase (PARP) were increased by incubation with either paclitaxel or cisplatin, suggesting that the apoptotic pathway was involved in cancer-drug-induced cell death.ConclusionsThese results may open up a novel therapeutic strategy for endometrial cancer: namely, the targeting of GRP78 to sensitize the tumor cell to chemotherapy.

► GRP78, which is induced by any kinds of stress against cell, is highly expressed in well-differentiated endometrial carcinoma. ► Estrogen induces GRP78 expression in well-differentiated endometrial carcinoma, resulting in increasing tumor proliferation. ► The expression level of GRP78 protein is one of key factors for chemosensitivity in endometrial cancer.