Abstract: Objective To investigate the therapeutic potential application of EeyarestatinI (EerI) and 4μ8C, the small-molecule inhibitors of UPR signaling pathway in the cervical cancer. Method The protein expression of GRP78/BiP, P97, Ubiquitin and IRE1α in normal cervical epithelia and cervical cancer were examined by immunohistochemistry. The effect of EerI and 4μ8C on HeLa cell proliferation and apoptosis were measured by MTS assay and flow cytometry, respectively. The combined antiproliferative effects of small-molecule inhibitors were carried out in combination of Bortezomib (BTZ) and Cisplatin (CDDP), respectively. Result GRP78/BiP, P97, Ubiquitin and IRE1α were significantly up-regulated in cervical cancer compared with normal cervical epithelia and displayed variability in the cervical cancer of different clinical stages (P<0.05). EerI and 4μ8C inhibited HeLa cell proliferation in a dose-dependent manner with inducing HeLa cell apoptosis in a similar fashion (P<0.05). MTS assays indicated that combination treatment significantly enhanced the antiproliferative effect of single chemotherapy drugs (P<0.05). Conclusion Small-molecule inhibitors targeting the key players of UPR show synergistic effects with other anticancer drugs, suggesting a new therapeutic strategy towards cervical cancer.

Key words: Key words: endoplasmic reticulum stress, cervical cancer, small-molecule inhibitor, combined anticancer therapeutics