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.
|Number of pages||6|
|Publication status||Published - 2021 Dec 10|
Bibliographical noteFunding Information:
This study was supported financially by the National Research Foundation of Korea (grant no. 2020R1A2C3003462 to I.S.) and KRIBB Research Initiative Program funded by the Ministry of Science ICT (MSIT) of Korea (S.‐K.K.).
© 2021 Wiley-VCH GmbH
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Organic Chemistry