ACSL4 is a predictive biomarker of sorafenib sensitivity in hepatocellular carcinoma

• Published in: Acta pharmacologica Sinica Vol. 42; no. 1; pp. 160 - 170
• Main Authors: Feng, Ji, Lu, Pei-zhi, Zhu, Guang-zhi, Hooi, Shing Chung, Wu, Yong, Huang, Xiao-wei, Dai, Hui-qi, Chen, Pan-hong, Li, Zhong-jie, Su, Wen-jing, Han, Chuang-ye, Ye, Xin-ping, Peng, Tao, Zhou, Jing, Lu, Guo-dong
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.01.2021; Nature Publishing Group
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Biomarkers; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Carcinoma, Hepatocellular - diagnosis; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell death; Cell Line, Tumor; Coenzyme A Ligases - genetics; Coenzyme A Ligases - metabolism; Ferroptosis; Ferroptosis - drug effects; Gene Knockout Techniques; Hepatocellular carcinoma; Humans; Immunology; Internal Medicine; Lipid peroxidation; Liver cancer; Liver Neoplasms - diagnosis; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Medical Microbiology; Mice; Mice, Inbred BALB C; Patients; Pharmacology/Toxicology; Prognosis; siRNA; Sorafenib - therapeutic use; Surgery; Targeted cancer therapy; Vaccine; Xenograft Model Antitumor Assays; Xenografts; ACSL4; ferroptosis; predictive biomarker; sorafenib; hepatocellular carcinoma
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-020-0439-x

Sorafenib is the first-line treatment of advanced hepatocellular carcinoma (HCC). However, there is a lack of validated biomarkers to predict sorafenib sensitivity. In this study we investigated the role of ACSL4, a positive-activating enzyme of ferroptosis, in sorafenib-induced cell death and HCC patient outcome. We showed that ACSL4 protein expression was negatively associated with IC 50 values of sorafenib in a panel of HCC cell lines ( R  = −0.952, P  < 0.001). Knockdown of ACSL4 expression by specific siRNA/sgRNA significantly attenuated sorafenib-induced lipid peroxidation and ferroptosis in Huh7 cells, and also rescued sorafenib-induced inhibition of xenograft tumor growth in vivo. We selected 29 HCC patients with surgery as primary treatment and sorafenib as postoperative adjunct therapy from a hospital-based cohort. A high proportion (66.7%) of HCC patients who had complete or partial responses to sorafenib treatment (according to the revised RECIST guideline) had higher ACSL4 expression in the pretreated HCC tissues, compared with those who had stable or progressed tumor growth (23.5%, P  = 0.029). Since ACSL4 expression was independent of sorafenib treatment, it could serve as a useful predictive biomarker. Taken together, this study demonstrates that ACSL4 is essential for sorafenib-induced ferroptosis and useful for predicting sorafenib sensitivity in HCC. This study may have important translational impacts in precise treatment of HCC.