Inhibiting endoplasmic reticulum stress and unfolded protein response: an effective strategy for chemoprevention of hepatocarcinogenesis

Endoplasmic reticulum stress and activation of the unfolded protein response are critical contributors to hepatocarcinogenesis. Targeting these pathways represents a novel strategy for liver cancer prevention. In this study, a hepatocarcinogenesis model was developed by administering Diethylnitrosamine (DEN) (50 mg/kg b.w, i.p) to male Wistar rats. The endogenous chaperone-inducer BIX was administered (0.1 mg/kg, bw, i.p) for the prevention of DEN-induced hepatocarcinogenesis. After 20 weeks of BIX treatment, its effect on tumor growth was assessed in terms of tumor statistics, tumor-dielectric properties and histopathology. The ER-stress inhibition potential of BIX was assessed using UPR-related genes and protein expression. The inflammatory, proliferative and apoptotic markers were assessed using enzyme immunoassay and fluorescent immunohistochemistry. BIX treatment impeded the growth of hepatic tumors, as demonstrated by decreased total number of tumors and tumor multiplicity. Histopathologically, the tumors in the BIX-protected group had lower histological grading as compared to untreated tumors. This was further supported by dielectric assessment of tumors, suggesting suppressed tumor development. BIX treatment significantly decreased the expression of UPR genes (PERK, ATF-6, CHOP) and proteins (p-PERK/PERK), respectively. Further, significantly decreased expression of inflammatory, proliferative and increased apoptotic markers confirmed the effectiveness of BIX in preventing ER stress-induced hepatocarcinogenesis. BIX effectively attenuated UPR activation and impeded tumor growth.