Bilirubin inhibits the anticancer activity of sorafenib by blocking MCL-1 degradation in hepatocellular carcinoma cells

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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1061-1077
Number of pages17
JournalCancer Biology and Medicine
Issue number7
StatePublished - Jul 15 2022


  • Apoptosis
  • bilirubin
  • hepatocellular carcinoma
  • MCL-1
  • sorafenib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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