2. Academic Validation
  3. ACSL4 is a predictive biomarker of sorafenib sensitivity in hepatocellular carcinoma

ACSL4 is a predictive biomarker of sorafenib sensitivity in hepatocellular carcinoma

  • Acta Pharmacol Sin. 2021 Jan;42(1):160-170. doi: 10.1038/s41401-020-0439-x.
Ji Feng  # 1,  Pei-Zhi Lu  # 1,  Guang-Zhi Zhu  # 2 3 4,  Shing Chung Hooi 5,  Yong Wu 1,  Xiao-Wei Huang 1,  Hui-Qi Dai 1,  Pan-Hong Chen 6,  Zhong-Jie Li 6,  Wen-Jing Su 1,  Chuang-Ye Han 2 3 4,  Xin-Ping Ye 2 3 4,  Tao Peng 7 8 9,  Jing Zhou 10 11,  Guo-Dong Lu 12 13 14 15
Affiliations

Affiliations

  • 1 Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, 530021, China.
  • 2 Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
  • 3 Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education (Guangxi Medical University), Nanning, 530021, China.
  • 4 Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Nanning, 530021, China.
  • 5 Department of Physiology, National University of Singapore, 2 Medical Drive, Singapore, 117593, Singapore.
  • 6 Department of Physiology, School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, China.
  • 7 Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China. p98720p@163.com.
  • 8 Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education (Guangxi Medical University), Nanning, 530021, China. p98720p@163.com.
  • 9 Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Nanning, 530021, China. p98720p@163.com.
  • 10 Department of Physiology, National University of Singapore, 2 Medical Drive, Singapore, 117593, Singapore. gardenia_zhou@hotmail.com.
  • 11 Department of Physiology, School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, China. gardenia_zhou@hotmail.com.
  • 12 Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, 530021, China. golden_lu@hotmail.com.
  • 13 Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education (Guangxi Medical University), Nanning, 530021, China. golden_lu@hotmail.com.
  • 14 Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, 530021, China. golden_lu@hotmail.com.
  • 15 Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore. golden_lu@hotmail.com.
  • # Contributed equally.
PMID: 32541921 DOI: 10.1038/s41401-020-0439-x
Abstract

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 IC50 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.

Keywords

ACSL4; ferroptosis; hepatocellular carcinoma; predictive biomarker; sorafenib.

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