Cargando…

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

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. Galec...

Descripción completa

Detalles Bibliográficos
Autores principales: Hsu, Tung-Wei, Su, Yen-Hao, Chen, Hsin-An, Liao, Po-Hsiang, Shen, Shih Chiang, Tsai, Kuei-Yen, Wang, Tzu-Hsuan, Chen, Alvin, Huang, Chih-Yang, Shibu, Marthandam Asokan, Wang, Wan-Yu, Shen, Shing-Chuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10373977/
https://www.ncbi.nlm.nih.gov/pubmed/37433225
http://dx.doi.org/10.18632/aging.204867
_version_ 1785078674683330560
author Hsu, Tung-Wei
Su, Yen-Hao
Chen, Hsin-An
Liao, Po-Hsiang
Shen, Shih Chiang
Tsai, Kuei-Yen
Wang, Tzu-Hsuan
Chen, Alvin
Huang, Chih-Yang
Shibu, Marthandam Asokan
Wang, Wan-Yu
Shen, Shing-Chuan
author_facet Hsu, Tung-Wei
Su, Yen-Hao
Chen, Hsin-An
Liao, Po-Hsiang
Shen, Shih Chiang
Tsai, Kuei-Yen
Wang, Tzu-Hsuan
Chen, Alvin
Huang, Chih-Yang
Shibu, Marthandam Asokan
Wang, Wan-Yu
Shen, Shing-Chuan
author_sort Hsu, Tung-Wei
collection PubMed
description 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.
format Online
Article
Text
id pubmed-10373977
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Impact Journals
record_format MEDLINE/PubMed
spelling pubmed-103739772023-07-28 Galectin-1-mediated MET/AXL signaling enhances sorafenib resistance in hepatocellular carcinoma by escaping ferroptosis Hsu, Tung-Wei Su, Yen-Hao Chen, Hsin-An Liao, Po-Hsiang Shen, Shih Chiang Tsai, Kuei-Yen Wang, Tzu-Hsuan Chen, Alvin Huang, Chih-Yang Shibu, Marthandam Asokan Wang, Wan-Yu Shen, Shing-Chuan Aging (Albany NY) Research Paper 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. Impact Journals 2023-07-11 /pmc/articles/PMC10373977/ /pubmed/37433225 http://dx.doi.org/10.18632/aging.204867 Text en Copyright: © 2023 Hsu et al. https://creativecommons.org/licenses/by/3.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Hsu, Tung-Wei
Su, Yen-Hao
Chen, Hsin-An
Liao, Po-Hsiang
Shen, Shih Chiang
Tsai, Kuei-Yen
Wang, Tzu-Hsuan
Chen, Alvin
Huang, Chih-Yang
Shibu, Marthandam Asokan
Wang, Wan-Yu
Shen, Shing-Chuan
Galectin-1-mediated MET/AXL signaling enhances sorafenib resistance in hepatocellular carcinoma by escaping ferroptosis
title Galectin-1-mediated MET/AXL signaling enhances sorafenib resistance in hepatocellular carcinoma by escaping ferroptosis
title_full Galectin-1-mediated MET/AXL signaling enhances sorafenib resistance in hepatocellular carcinoma by escaping ferroptosis
title_fullStr Galectin-1-mediated MET/AXL signaling enhances sorafenib resistance in hepatocellular carcinoma by escaping ferroptosis
title_full_unstemmed Galectin-1-mediated MET/AXL signaling enhances sorafenib resistance in hepatocellular carcinoma by escaping ferroptosis
title_short Galectin-1-mediated MET/AXL signaling enhances sorafenib resistance in hepatocellular carcinoma by escaping ferroptosis
title_sort galectin-1-mediated met/axl signaling enhances sorafenib resistance in hepatocellular carcinoma by escaping ferroptosis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10373977/
https://www.ncbi.nlm.nih.gov/pubmed/37433225
http://dx.doi.org/10.18632/aging.204867
work_keys_str_mv AT hsutungwei galectin1mediatedmetaxlsignalingenhancessorafenibresistanceinhepatocellularcarcinomabyescapingferroptosis
AT suyenhao galectin1mediatedmetaxlsignalingenhancessorafenibresistanceinhepatocellularcarcinomabyescapingferroptosis
AT chenhsinan galectin1mediatedmetaxlsignalingenhancessorafenibresistanceinhepatocellularcarcinomabyescapingferroptosis
AT liaopohsiang galectin1mediatedmetaxlsignalingenhancessorafenibresistanceinhepatocellularcarcinomabyescapingferroptosis
AT shenshihchiang galectin1mediatedmetaxlsignalingenhancessorafenibresistanceinhepatocellularcarcinomabyescapingferroptosis
AT tsaikueiyen galectin1mediatedmetaxlsignalingenhancessorafenibresistanceinhepatocellularcarcinomabyescapingferroptosis
AT wangtzuhsuan galectin1mediatedmetaxlsignalingenhancessorafenibresistanceinhepatocellularcarcinomabyescapingferroptosis
AT chenalvin galectin1mediatedmetaxlsignalingenhancessorafenibresistanceinhepatocellularcarcinomabyescapingferroptosis
AT huangchihyang galectin1mediatedmetaxlsignalingenhancessorafenibresistanceinhepatocellularcarcinomabyescapingferroptosis
AT shibumarthandamasokan galectin1mediatedmetaxlsignalingenhancessorafenibresistanceinhepatocellularcarcinomabyescapingferroptosis
AT wangwanyu galectin1mediatedmetaxlsignalingenhancessorafenibresistanceinhepatocellularcarcinomabyescapingferroptosis
AT shenshingchuan galectin1mediatedmetaxlsignalingenhancessorafenibresistanceinhepatocellularcarcinomabyescapingferroptosis