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Targeting VPS41 induces methuosis and inhibits autophagy in cancer cells

Yue Liu1, Yong Sun1, Yuliang Xu1

  • 1Department of Natural Products Chemistry, Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.

Cell Chemical Biology
|January 28, 2023
PubMed

Insights

Methyl 2,4-dihydroxy-3-(3-methyl-2-butenyl)-6-phenethylbenzoate (DMBP) targets vacuolar protein sorting-associated protein 41 homolog (VPS41), inhibiting cancer cell proliferation via methuosis and restraining metastasis.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Drug Discovery

Background:

  • The homotypic fusion and vacuole protein sorting (HOPS) complex is crucial for membrane trafficking in cellular processes like endocytosis and autophagy.
  • Dysfunction of HOPS subunits is linked to cancer, yet their therapeutic potential remains underexplored.

Purpose of the Study:

  • To investigate the anticancer mechanisms of methyl 2,4-dihydroxy-3-(3-methyl-2-butenyl)-6-phenethylbenzoate (DMBP).
  • To identify vacuolar protein sorting-associated protein 41 homolog (VPS41) as a key target of DMBP in cancer cells.

Main Methods:

  • Identified VPS41 as a direct target of the natural compound DMBP.
  • Investigated DMBP's effects on cancer cell phenotypes, including methuosis induction and autophagic flux inhibition.
  • Assessed DMBP's efficacy in a mouse model of metastatic melanoma.

Main Results:

  • DMBP inhibits VPS41 function, leading to methuosis and impaired autophagic flux in cancer cells.
  • DMBP restricts the fusion of late endosomes and autophagosomes with lysosomes.
  • DMBP demonstrated significant inhibition of metastasis in a preclinical mouse model.

Conclusions:

  • Targeting VPS41 with DMBP represents a novel therapeutic strategy against cancer proliferation.
  • DMBP-induced methuosis offers a potential pathway for developing new anticancer treatments.
Keywords:
HOPS complexVPS41autophagycytoplasmic vacuolizationliverwortsmethuosismicropinocytosis

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