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.

Leyi Yao;Qian Zhao;Ding Yan;Ziying Lei;Yali Hao;Jinghong Chen;Qian Xue;Xiaofen Li;Qingtian Huang;Daolin Tang;Q.Ping Dou;Xin Chen;Jinbao Liu

Affiliated Cancer Hospital&Institute of Guangzhou Medical University,Guangzhou 510095,China;Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation,State Key Laboratory of Respiratory Disease,School of Basic Medical Sciences,Guangzhou Medical University,Guangzhou 511436,China;Institute of Digestive Disease of Guangzhou Medical University,The Sixth Affiliated Hospital of Guangzhou Medical University,Qingyuan People's Hospital,Qingyuan 511518,China;School of Public Health,Guangzhou Medical University,Guangzhou,511436,China;Department of Surgery,UT Southwestern Medical Center,Dallas,TX 75390,USA;Barbara Ann Karmanos Cancer Institute and Departments of Oncology,Pharmacology&Pathology,School of Medicine,Wayne State University,Detroit,MI 48201,USA

癌症生物学与医学（英文版）

[1]Leyi Yao;Qian Zhao;Ding Yan;Ziying Lei;Yali Hao;Jinghong Chen;Qian Xue;Xiaofen Li;Qingtian Huang;Daolin Tang;Q.Ping Dou;Xin Chen;Jinbao Liu-.Bilirubin inhibits the anticancer activity of sorafenib by blocking MCL-1 degradation in hepatocellular carcinoma cells)[J].癌症生物学与医学（英文版）,2022(07):1061-1077

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