General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China.
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Cell Rep. 2022 Apr 19;39(3):110712. doi: 10.1016/j.celrep.2022.110712.
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.
受体酪氨酸激酶（RTKs）的异常激活及其随后的代谢重编程在癌症进展中起着关键作用。我们之前的研究表明，高尔基膜蛋白 1（GOLM1）通过增强 RTKs 的循环利用促进肝细胞癌（HCC）的转移。然而，这个 RTK 循环过程是如何被调控并与 RTK 降解偶联的仍然知之甚少。在这里，我们证明胆固醇以 GOLM1 依赖的方式抑制 RTKs 的自噬降解。进一步的机制研究表明，GOLM1 通过与 LC3 相互作用的区域（LIR）与 LC3 相互作用，介导 RTKs 的选择性自噬，该区域受胆固醇-mTORC1 轴调控。他汀类药物降低胆固醇可提高多种酪氨酸激酶抑制剂（TKI）在体内的疗效。我们的研究结果表明，胆固醇作为一种信号，可将 GOLM1-RTK 降解切换为 GOLM1-RTK 循环，并提示通过他汀类药物降低胆固醇可能是提高 HCC 中 TKI 效率的一种有前途的联合策略。
