TRIM3 modulates cisplmatin-resistant of cervical squamous cell carcinoma via endoplasmic reticulum stress signaling in vitro.

Abstract

TRIM3 is widely recognized as a tumor suppressor gene. However, its precise role in cervical squamous cell carcinoma (CESC) remains elusive. Here, we observed a significant decrease in the expression of TRIM3 in CESC cells. Overexpression of TRIM3 suppresses cell proliferation and clonal formation. Through the establishment of cisplatin (cDDP)-resistant CESC cell lines, we discovered that the expression of TRIM3 was further downregulated in cDDP-resistant cells, while overexpression of TRIM3 enhanced cellular sensitivity to cDDP. Mechanistic investigations revealed that TRIM3 directly interacts with GRP78, a crucial protein involved in endoplasmic reticulum stress (ERS) pathway, promoting its ubiquitination degradation. Under cDDP treatment, the overexpression of TRIM3 in cDDP-resistant cells suppressed cell proliferation and downregulated the expression of drug-resistant genes, while simultaneously enhancing the activation of apoptosis signaling pathways. However, co-expression of TRIM3 and GRP78 restored cellular sensitivity to cDDP back to normal levels. Consequently, overexpressing TRIM3 in drug-resistant cells facilitates PERK activation and subsequent induction of apoptosis through inhibition of GRP78, ultimately suppressing drug resistance and inducing apoptosis in CESC cells. In conclution, our study suggests that the TRIM3/GRP78 axis regulates cDDP resistance in CESC cells by modulating the downstream apoptotic pathway of ERS.