Bilirubin Restrains the Anticancer Effect of Vemurafenib on BRAF-Mutant Melanoma Cells Through ERK-MNK1 Signaling

Frontiers in Oncology

Xizhi Wen¹  Daolin Tang¹  Jiawen Wu¹  Guanmei Wen²  Xiaoyu Zhong²  Yufan Tan²  Wenshuang Sun²  Yuning Liao²  Jinbao Liu²  Xiaoshi Zhang²  Zhenlong Shao³  Leyi Yao⁴ 

[1] Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China;;Affiliated Cancer Hospital &Biotherapy Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China;Institute of Digestive Disease of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, China;

关键词: bilirubin;    vemurafenib;    ERK;    MNK1;    BRAF-mutant melanoma;   

DOI  :  10.3389/fonc.2021.698888

来源: DOAJ

【 摘 要 】

Melanoma, the most threatening cancer in the skin, has been considered to be driven by the carcinogenic RAF-MEK1/2-ERK1/2 signaling pathway. This signaling pathway is usually mainly dysregulated by mutations in BRAF or RAS in skin melanomas. Although inhibitors targeting mutant BRAF, such as vemurafenib, have improved the clinical outcome of melanoma patients with BRAF mutations, the efficiency of vemurafenib is limited in many patients. Here, we show that blood bilirubin in patients with BRAF-mutant melanoma treated with vemurafenib is negatively correlated with clinical outcomes. In vitro and animal experiments show that bilirubin can abrogate vemurafenib-induced growth suppression of BRAF-mutant melanoma cells. Moreover, bilirubin can remarkably rescue vemurafenib-induced apoptosis. Mechanically, the activation of ERK-MNK1 axis is required for bilirubin-induced reversal effects post vemurafenib treatment. Our findings not only demonstrate that bilirubin is an unfavorable for patients with BRAF-mutant melanoma who received vemurafenib treatment, but also uncover the underlying mechanism by which bilirubin restrains the anticancer effect of vemurafenib on BRAF-mutant melanoma cells.

【 授权许可】

Unknown