ARP101, a selective MMP-2 inhibitor, induces autophagy-associated cell death in cancer cells |
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Authors: | Jo Yoon Kyung Park So Jung Shin Ji Hyun Kim Yunha Hwang Jung Jin Cho Dong-Hyung Kim Jin Cheon |
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Institution: | aInstitute for Innovative Cancer Research, Asan Medical Center, Seoul 138-736, Republic of Korea;bDepartment of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea;cGraduate School of East-West Medical Science, Kyung Hee University, Gyeoggi-Do 446-701, Republic of Korea |
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Abstract: | Autophagy is a catabolic cellular process involving self-digestion and turnover of macromolecules and entire organelles. Autophagy is primarily a protective process in response to cellular stress, but it can be associated with cell death. Genetic evidence also supports autophagy function as a tumor suppressor mechanism. To identify specific regulators to autophagy, we screened the Lopac 1280 and the Prestwick chemical libraries using a cell-based screening system with autophagy marker (green fluorescence protein conjugated LC3 protein (GFP-LC3)). We identified ARP101, a selective matrix metalloproteinase-2 (MMP-2) inhibitor as one of the most potent inducer of autophagy. ARP101 treatment was highly effective in inducing the formation of autophagosome and conversion of LC3I into LC3II. Moreover, ARP101-induced autophagy was completely blocked in mouse embryo fibroblasts that lacked autophagy related gene 5 (ATG5−/− MEF). Interestingly, cell death induced by ARP101 was not inhibited by zVAD, a pan caspase inhibitor, whereas, it was efficiently suppressed by addition of 3-methyladenine, an autophagy inhibitor. These results suggest that the selective MMP-2 inhibitor, ARP101, induces autophagy and autophagy-associated cell death. |
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Keywords: | Autophagy ATG5 Cell death ARP101 Cancer cell |
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