An Autophagy-Disrupting Small Molecule Promotes Cancer Cell Death via Caspase Activation

Sang Hyun Park, Insu Shin, Gun Hee Kim, Sung Kyun Ko, Injae Shin

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

A novel autophagy inhibitor, autophazole (Atz), which promoted cancer cell death via caspase activation, is described. This compound was identified from cell-based high-content screening of an imidazole library. The results showed that Atz was internalized into lysosomes of cells where it induced lysosomal membrane permeabilization (LMP). This process generated nonfunctional autolysosomes, thereby inhibiting autophagy. In addition, Atz was found to promote LMP-mediated apoptosis. Specifically, LMP induced by Atz caused release of cathepsins from lysosomes into the cytosol. Cathepsins in the cytosol cleaved Bid to generate tBid, which subsequently activated Bax to induce mitochondrial outer membrane permeabilization (MOMP). This event led to cancer cell death via caspase activation. Overall, the findings suggest that Atz will serve as a new chemical probe in efforts aimed at gaining a better understanding of the autophagic process.

Original languageEnglish
Pages (from-to)3425-3430
Number of pages6
JournalChemBioChem
Volume22
Issue number24
DOIs
Publication statusPublished - 2021 Dec 10

Bibliographical note

Publisher Copyright:
© 2021 Wiley-VCH GmbH

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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