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  3. Carbonic anhydrase 2 facilitates sorafenib resistance by counteracting MCT4-mediated intracellular pH dysregulation in HCC

Carbonic anhydrase 2 facilitates sorafenib resistance by counteracting MCT4-mediated intracellular pH dysregulation in HCC

  • Cell Rep. 2024 Dec 24;43(12):114996. doi: 10.1016/j.celrep.2024.114996.
Hui Lu 1,  Huiya Liu 2,  Ronghui Yan 2,  Wenhao Ma 2,  Haiying Liu 2,  Rui Liu 2,  Yuchen Sun 2,  Ling Ye 2,  Ping Gao 3,  Weidong Jia 2,  Pinggen Zhang 4,  Huafeng Zhang 5
Affiliations

Affiliations

  • 1 Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
  • 2 Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 3 Southern Medical University, Guangzhou, China.
  • 4 Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, University of Science and Technology of China, Hefei, Anhui, China. Electronic address: zhangpp@ustc.edu.cn.
  • 5 Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, University of Science and Technology of China, Hefei, Anhui, China. Electronic address: hzhang22@ustc.edu.cn.
PMID: 39607826 DOI: 10.1016/j.celrep.2024.114996
Abstract

Sorafenib, the targeted therapy for hepatocellular carcinoma (HCC), has been utilized in clinics for over a decade. However, its effectiveness is severely hindered by acquired drug resistance, the mechanisms of which remain largely elusive. In this study, we identify that Carbonic Anhydrase 2 (CA2) is a key regulator of sorafenib resistance. Mechanistically, sorafenib treatment decreases intracellular pH (pHi) by suppressing Monocarboxylate Transporter 4 (MCT4) expression, while high levels of CA2 counteract MCT4-mediated pHi dysregulation upon sorafenib treatment, maintaining pHi homeostasis to facilitate cell survival and sorafenib resistance. Targeting CA2 re-sensitizes resistant HCC cells to sorafenib both in vitro and in vivo. Importantly, analysis of clinical samples shows a strong correlation between CA2 expression levels and the therapeutic efficacy of sorafenib in HCC patients. Our findings highlight the significance of CA2 in facilitating sorafenib resistance and propose targeting CA2 as a potential strategy for overcoming sorafenib resistance in HCC patients.

Keywords

CA2; CP: Cancer; HCC organoids; Hepatocellular carcinoma; Intracellular pH homeostasis; Sorafenib resistance.

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