2. Academic Validation
  3. Cholesterol suppresses GOLM1-dependent selective autophagy of RTKs in hepatocellular carcinoma

Cholesterol suppresses GOLM1-dependent selective autophagy of RTKs in hepatocellular carcinoma

  • Cell Rep. 2022 Apr 19;39(3):110712. doi: 10.1016/j.celrep.2022.110712.
Wei-Qing Shao 1,  Wen-Wei Zhu 1,  Meng-Jun Luo 2,  Ming-Hao Fan 1,  Qin Li 3,  Sheng-Hao Wang 1,  Zhi-Fei Lin 1,  Jing Zhao 1,  Yan Zheng 4,  Qiong-Zhu Dong 4,  Lu Lu 1,  Hu-Liang Jia 1,  Ju-Bo Zhang 5,  Ming Lu 6,  Jin-Hong Chen 7,  Lun-Xiu Qin 8
Affiliations

Affiliations

  • 1 General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China.
  • 2 Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 3 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China.
  • 4 General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
  • 5 Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 6 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: mlu@sibs.ac.cn.
  • 7 General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China. Electronic address: jinhongch@hotmail.com.
  • 8 General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: qinlx@fudan.edu.cn.
PMID: 35443161 DOI: 10.1016/j.celrep.2022.110712
Abstract

Aberrant activation of Receptor Tyrosine Kinases (RTKs) and the subsequent metabolic reprogramming play critical roles in Cancer progression. Our previous study has shown that Golgi membrane protein 1 (GOLM1) promotes hepatocellular carcinoma (HCC) metastasis by enhancing the recycling of RTKs. However, how this RTK recycling process is regulated and coupled with RTK degradation remains poorly defined. Here, we demonstrate that Cholesterol suppresses the autophagic degradation of RTKs in a GOLM1-dependent manner. Further mechanistic studies reveal that GOLM1 mediates the selective Autophagy of RTKs by interacting with LC3 through an LC3-interacting region (LIR), which is regulated by a cholesterol-mTORC1 axis. Lowering Cholesterol by statins improves the efficacy of multiple tyrosine kinase inhibitors (TKIs) in vivo. Our findings indicate that Cholesterol serves as a signal to switch GOLM1-RTK degradation to GOLM1-RTK recycling and suggest that lowering Cholesterol by statin may be a promising combination strategy to improve the TKI efficiency in HCC.

Keywords

CP: Cancer; CP: Cell biology; cholesterol metabolism; liver cancer; lysosomal degradation; statin; tyrosine kinase inhibitor.

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