The Roles of GSK-3β in Regulation of Retinoid Signaling and Sorafenib Treatment Response in Hepatocellular Carcinoma

• Published in: Theranostics Vol. 10; no. 3; pp. 1230 - 1244
• Main Authors: Zhang, Shuaishuai, Gao, Weiwei, Tang, Juan, Zhang, Huaifang, Zhou, Yuqi, Liu, Jie, Chen, Kun, Liu, Fangzhou, Li, Wengang, To, Sally K Y, Wong, Alice Sze Tsai, Zhang, Xiao-Kun, Zhou, Hu, Zeng, Jin-Zhang
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 2020; Ivyspring International Publisher
• Subjects: Animals; Antibodies; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Cell Survival - drug effects; E coli; Glycogen Synthase Kinase 3 beta - physiology; HEK293 Cells; Hep G2 Cells; Homeostasis; Humans; Kinases; Liver cancer; Liver Neoplasms, Experimental - drug therapy; Liver Neoplasms, Experimental - metabolism; Male; Metabolism; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Phosphorylation; Plasmids; Proteins; Receptors, Retinoic Acid - metabolism; Research Paper; Retinoic Acid Receptor alpha - metabolism; Retinoid X Receptor beta - metabolism; Sorafenib - pharmacology; Sorafenib - therapeutic use; Targeted cancer therapy; Tretinoin - metabolism; Tumors; China; GSK-3β; Retinoid Receptor; Target Therapy; Hepatocellular Carcinoma
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.38711

: Glycogen synthase kinase-3β (GSK-3β) plays key roles in metabolism and many cellular processes. It was recently demonstrated that overexpression of GSK-3β can confer tumor growth. However, the expression and function of GSK-3β in hepatocellular carcinoma (HCC) remain largely unexplored. This study is aimed at investigating the role and therapeutic target value of GSK-3β in HCC. : We firstly clarified the expression of GSK-3β in human HCC samples. Given that deviated retinoid signalling is critical for HCC development, we studied whether GSK-3β could be involved in the regulation. Since sorafenib is currently used to treat HCC, the involvement of GSK-3β in sorafenib treatment response was determined. Co-immunoprecipitation, GST pull down, kinase assay, luciferase reporter and chromatin immunoprecipitation were used to explore the molecular mechanism. The biological readouts were examined with MTT, flow cytometry and animal experiments. : We demonstrated that GSK-3β is highly expressed in HCC and associated with shorter overall survival (OS). Overexpression of GSK-3β confers HCC cell colony formation and xenograft tumor growth. Tumor-associated GSK-3β is correlated with reduced expression of retinoic acid receptor-β (RARβ), which is caused by GSK-3β-mediated phosphorylation and heterodimerization abrogation of retinoid X receptor (RXRα) with RARα on RARβ promoter. Overexpression of functional GSK-3β impairs retinoid response and represses sorafenib anti-HCC effect. Inactivation of GSK-3β by tideglusib can potentiate 9- -RA enhancement of sorafenib sensitivity (tumor inhibition from 48.3% to 93.4%). Efficient induction of RARβ by tideglusib/9- RA is required for enhanced therapeutic outcome of sorafenib, which effect is greatly inhibited by knocking down RARβ. : Our findings demonstrate that GSK-3β is a disruptor of retinoid signalling and a new resistant factor of sorafenib in HCC. Targeting GSK-3β may be a promising strategy for HCC treatment in clinic.