Targeting VPS41 induces methuosis and inhibits autophagy in cancer cells.

Yue Liu, Yong Sun, Yuliang Xu, Ting Dong, Lilin Qian, Hongbo Zheng, Yun Gao, Zhaojun Chu, Xiaojie Fu, Hanrui Zhang, Feng Xie, Chunyang Zhang, Yajie Tang, Hongxiang Lou

Cell chemical biology 2023 Feb 16

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The homotypic fusion and vacuole protein sorting (HOPS) complex mediates membrane trafficking involved in endocytosis, autophagy, lysosome biogenesis, and phagocytosis. Defects in HOPS subunits are associated with various forms of cancer, but their potential as drug targets has rarely been examined. Here, we identified vacuolar protein sorting-associated protein 41 homolog (VPS41), a subunit of the HOPS complex, as a target of methyl 2,4-dihydroxy-3-(3-methyl-2-butenyl)-6-phenethylbenzoate (DMBP), a natural small molecule with preferable anticancer activity. DMBP induced methuosis and inhibited autophagic flux in cancer cells by inhibiting the function of VPS41, leading to the restrained fusion of late endosomes and autophagosomes with lysosomes. Moreover, DMBP effectively inhibited metastasis in a mouse metastatic melanoma model. Collectively, the current work revealed that targeting VPS41 would provide a valuable method of inhibiting cancer proliferation through methuosis. Copyright © 2023 Elsevier Ltd. All rights reserved.

Citation

Yue Liu, Yong Sun, Yuliang Xu, Ting Dong, Lilin Qian, Hongbo Zheng, Yun Gao, Zhaojun Chu, Xiaojie Fu, Hanrui Zhang, Feng Xie, Chunyang Zhang, Yajie Tang, Hongxiang Lou. Targeting VPS41 induces methuosis and inhibits autophagy in cancer cells. Cell chemical biology. 2023 Feb 16;30(2):130-143.e5