TY - JOUR T1 - Bilirubin inhibits the anticancer activity of sorafenib by blocking MCL-1 degradation in hepatocellular carcinoma cells JF - Cancer Biology & Medicine JO - Cancer Biology & Medicine SP - 1061 LP - 1077 DO - 10.20892/j.issn.2095-3941.2021.0598 VL - 19 IS - 7 AU - Leyi Yao AU - Qian Zhao AU - Ding Yan AU - Ziying Lei AU - Yali Hao AU - Jinghong Chen AU - Qian Xue AU - Xiaofen Li AU - Qingtian Huang AU - Daolin Tang AU - Q. Ping Dou AU - Xin Chen AU - Jinbao Liu Y1 - 2022/07/15 UR - http://www.cancerbiomed.org/content/19/7/1061.abstract N2 - Objective: Sorafenib is a first-line drug for advanced hepatocellular carcinoma (HCC). Unfortunately, most patients with HCC do not respond to sorafenib, mainly because of the frequent development of drug resistance. Bilirubin is an end metabolite of heme catabolism and an indicator of liver function, but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear. In the current study, we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC.Methods: A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC. Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin, and cell proliferation, apoptosis, and signaling pathways were assayed. The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts.Results: Serum levels of bilirubin (including total, direct, and indirect bilirubin) negatively correlated with the overall survival of patients with HCC treated with sorafenib (P < 0.05). Both in vitro and in vivo analyses demonstrated that bilirubin significantly abrogated sorafenib-mediated proliferation inhibition and apoptosis induction in HCC cells (P < 0.05). Mechanically, bilirubin inhibited sorafenib-induced activation of GSK-3β and subsequent downstream MCL-1 degradation.Conclusions: Our study provides experimental evidence of the antagonistic effect of bilirubin toward sorafenib-mediated anticancer activity in HCC, and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatment. ER -