An Autophagy-Disrupting Small Molecule Promotes Cancer Cell Death via Caspase Activation |
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Authors: | Sang-Hyun Park Insu Shin Dr Gun-Hee Kim Dr Sung-Kyun Ko Prof?Dr Injae Shin |
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Affiliation: | 1. Department of Chemistry, Yonsei University, Seoul, 03722 South Korea;2. Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, 28116 South Korea |
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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. |
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Keywords: | autophagy apoptosis cancer cell death high-throughput screening small molecules |
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