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Upregulation of CSNK1A1 induced by ITGB5 confers to hepatocellular carcinoma resistance to sorafenib in vivo by disrupting the EPS15/EGFR complex

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机构： [1]Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China [2]Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China [3]Uro-Oncology Institute of Central South University, Changsha, Hunan 410011, China [4]Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China [5]Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province & Organ Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 611731 Sichuan, China [6]Hepatobiliary and Pancreatic Surgery Department, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 611731, Sichuan, China [7]Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, Sichuan, China

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Oral multitarget tyrosine kinase inhibitors (TKIs), such as sorafenib, which suppress tumor cell proliferation and tumor angiogenesis, have been approved to treat patients with hepatocellular carcinoma (HCC). Of note, only approximately 30% of patients can benefit from TKIs, and this population usually acquires drug resistance within 6 months. In this study, we intended to explore the mechanism associated with regulating the sensitivity of HCC to TKIs. We revealed that integrin subunit β 5 (ITGB5) is abnormally expressed in HCC and contributes to decreased the sensitivity of HCC to sorafenib. Mechanistically, unbiased mass spectrometry analysis using ITGB5 antibodies revealed that ITGB5 interacts with EPS15 to prevent the degradation of EGFR in HCC cells, which activates AKT-mTOR signaling and the MAPK pathway to reduce the sensitivity of HCC cells to sorafenib. In addition, mass spectrometry analysis showed that CSNK1A1 binds to ITGB5 in HCC cells. Further study indicated that ITGB5 increased the protein level of CSNK1A1 through the EGFR-AKT-mTOR pathway in HCC. Upregulated CSNK1A1 phosphorylates ITGB5 to enhance the interaction between ITGB5 and EPS15 and activate EGFR in HCC cells. Thus, we identified a positive feedback loop between ITGB5-EPS15-EGFR-CSNK1A1 in HCC cells. This finding provides a theoretical basis for the future development of therapeutic strategies to improve the anti-HCC efficacy of sorafenib.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

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出版当年[2023]版：

大类 | 2 区

医学

小类 | 1 区药学

最新[2023]版：

大类 | 2 区

医学

小类 | 1 区药学

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出版当年[2023]版：

Q1 PHARMACOLOGY & PHARMACY

最新[2023]版：

Q1 PHARMACOLOGY & PHARMACY

影响因子： 9.1 最新[2023版] 9 最新五年平均 9.1 出版当年[2023版] 9 出版当年五年平均 9.3 出版前一年[2022版]

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第一作者机构： [1]Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China

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通讯机构： [6]Hepatobiliary and Pancreatic Surgery Department, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 611731, Sichuan, China [7]Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, Sichuan, China [*1]Hepatobiliary and Pancreatic Surgery Department, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 611731, Sichuan, China.

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