1. Academic Validation
  2. Cholesterol sensor SCAP contributes to sorafenib resistance by regulating autophagy in hepatocellular carcinoma

Cholesterol sensor SCAP contributes to sorafenib resistance by regulating autophagy in hepatocellular carcinoma

  • J Exp Clin Cancer Res. 2022 Mar 30;41(1):116. doi: 10.1186/s13046-022-02306-4.
Danyang Li  # 1 Yingcheng Yao  # 1 Yuhan Rao 1 Xinyu Huang 1 Li Wei 1 Zhimei You 2 Guo Zheng 1 Xiaoli Hou 1 Yu Su 1 Zac Varghese 3 John F Moorhead 3 Yaxi Chen 4 Xiong Z Ruan 5 6
Affiliations

Affiliations

  • 1 Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China.
  • 2 Department of General Medicine, Affiliated Cancer Hospital of Chongqing University, Chongqing, 400016, China.
  • 3 John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London, London, NW3 2PF, UK.
  • 4 Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China. chenyaxi@cqmu.edu.cn.
  • 5 Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China. x.ruan@ucl.ac.uk.
  • 6 John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London, London, NW3 2PF, UK. x.ruan@ucl.ac.uk.
  • # Contributed equally.
Abstract

Background: Hepatocellular carcinoma (HCC) is one of the most malignant tumors and the fourth leading cause of cancer-related death worldwide. Sorafenib is currently acknowledged as a standard therapy for advanced HCC. However, acquired resistance substantially limits the clinical efficacy of sorafenib. Therefore, further investigations of the associated risk factors are highly warranted.

Methods: We analysed a group of 78 HCC patients who received sorafenib treatment after liver resection surgery. The expression of SCAP and its correlation with sorafenib resistance in HCC clinical samples were determined by immunohistochemical analyses. Overexpression and knockdown approaches in vitro were used to characterize the functional roles of SCAP in regulating sorafenib resistance. The effects of SCAP inhibition in HCC cell lines were analysed in proliferation, Apoptosis, and colony formation assays. Autophagic regulation by SCAP was assessed by immunoblotting, immunofluorescence and immunoprecipitation assays. The combinatorial effect of a SCAP inhibitor and sorafenib was tested using nude mice.

Results: Hypercholesterolemia was associated with sorafenib resistance in HCC treatment. The degree of sorafenib resistance was correlated with the expression of the Cholesterol sensor SCAP and consequent deposition of Cholesterol. SCAP is overexpressed in HCC tissues and hepatocellular carcinoma cell lines with sorafenib resistance, while SCAP inhibition could improve sorafenib sensitivity in sorafenib-resistant HCC cells. Furthermore, we found that SCAP-mediated sorafenib resistance was related to decreased Autophagy, which was connected to decreased AMPK activity. A clinically significant finding was that lycorine, a specific SCAP inhibitor, could reverse acquired resistance to sorafenib in vitro and in vivo.

Conclusions: SCAP contributes to sorafenib resistance through AMPK-mediated autophagic regulation. The combination of sorafenib and SCAP targeted therapy provides a novel personalized treatment to enhance sensitivity in sorafenib-resistant HCC.

Keywords

Autophagy; Hepatocellular carcinoma (HCC); Lycorine; SCAP; Sorafenib resistant.

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