Aging
Navigate
Submit an Article
Research Paper|Volume 15, Issue 13|pp 6503—6525

Galectin-1-mediated MET/AXL signaling enhances sorafenib resistance in hepatocellular carcinoma by escaping ferroptosis

Tung-Wei Hsu1,2, Yen-Hao Su2,3,4,5, Hsin-An Chen2,3,4,5, Po-Hsiang Liao2, Shih Chiang Shen2,3,4,5,6,7, Kuei-Yen Tsai2,4,6, Tzu-Hsuan Wang2, Alvin Chen2, Chih-Yang Huang8,9,10,11, Marthandam Asokan Shibu12, Wan-Yu Wang2, Shing-Chuan Shen1,13,14
  • 1Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
  • 2Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
  • 3TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
  • 4Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
  • 5TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei 11031, Taiwan
  • 6Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
  • 7Metabolic and Weight Management Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
  • 8Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan
  • 9Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 97002, Taiwan
  • 10Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan
  • 11Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
  • 12Department of Biotechnology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
  • 13Department of Dermatology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
  • 14International Master/PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
Received: March 24, 2023Accepted: June 9, 2023Published: July 11, 2023
https://doi.org/10.18632/aging.204867

Copyright: © 2023 Hsu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Sorafenib, a small-molecule inhibitor targeting several tyrosine kinase pathways, is the standard treatment for advanced hepatocellular carcinoma (HCC). However, not all patients with HCC respond well to sorafenib, and 30% of patients develop resistance to sorafenib after short-term treatment. Galectin-1 modulates cell-cell and cell-matrix interactions and plays a crucial role in HCC progression. However, whether Galectin-1 regulates receptor tyrosine kinases by sensitizing HCC to sorafenib remains unclear. Herein, we established a sorafenib-resistant HCC cell line (Huh-7/SR) and determined that Galectin-1 expression was significantly higher in Huh-7/SR cells than in parent cells. Galectin-1 knockdown reduced sorafenib resistance in Huh-7/SR cells, whereas Galectin-1 overexpression in Huh-7 cells increased sorafenib resistance. Galectin-1 regulated ferroptosis by inhibiting excessive lipid peroxidation, protecting sorafenib-resistant HCC cells from sorafenib-mediated ferroptosis. Galectin-1 expression was positively correlated with poor prognostic outcomes for HCC patients. Galectin-1 overexpression promoted the phosphorylation of AXL receptor tyrosine kinase (AXL) and MET proto-oncogene, receptor tyrosine kinase (MET) signaling, which increased sorafenib resistance. MET and AXL were highly expressed in patients with HCC, and AXL expression was positively correlated with Galectin-1 expression. These findings indicate that Galectin-1 regulates sorafenib resistance in HCC cells through AXL and MET signaling. Consequently, Galectin-1 is a promising therapeutic target for reducing sorafenib resistance and sorafenib-mediated ferroptosis in patients with HCC.