CLINICOPATHOLOGIC CHARACTERIZATION OF SORAFENIB-INDUCED ENDOPLASMIC RETICULUM STRESS IN HUMAN LIVER CANCER CELLS

Sorafenib (Sor) is clinical standard therapy for advanced hepatocellular carcinoma (HCC). However, detailed molecular mechanism behind Sor-exerted pharmacological effect remains unknown. In this study, sera samples, staged hepatic cancer tissues from Sor-treated patients with advanced HCC were harvested for a group of biochemical tests and immunoassays. Compared to non-treated control, blood contents of alanine transaminase (ALT), aspartate transaminase (AST), alpha-fetoprotein (AFP), fibroblast growth factor 21 (FGF21) were decreased in Sor-treated HCC patients, while the level of interleukin 10 (IL-10) were increased. As well, reduced triglyceride (TG), total cholesterol (T-CHOL), interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) levels in sera were checked in Sor-treated HCC patients. In comparison with non-treated cancer sections, Sor-treated HCC cells showed decreased positive cells of proliferative marker for proliferating cell nuclear antigen (PCNA) and metastasized biomarker for cytokeratin 19 (CK19). In addition, elevated immunofluorescence-labeled cells of endoplasmic reticulum (ER)-stress markers of activating transcription factor 6 (ATF6), eukaryotic initiation factor 2 alpha kinase (eIF2 alpha), glucose-regulated protein (GRP-78), X-box binding protein 1 (XBP1) were observed in Sor-treated HCC livers. Further, validated data from Western blot assay exhibited that hepatocellular expressions of ATF6, eIF2 alpha, GRP78, XBP1 in Sor-treated HCC liver cells were up-regulated. Briefly, our present clinicopathologic findings indicate that Sor-induced ER stress may be responsible for therapeutic mechanism against advanced HCC. In addition, induction of intracellular ER stress functions as a promising strategy for treating advanced HCC.