ARP101, a selective MMP-2 inhibitor, induces autophagy-associated cell death in cancer cells

• Published in: Biochemical and biophysical research communications 2011-01, Vol.404 (4), p.1039-1043
• Main Authors: Jo, Yoon Kyung, Park, So Jung, Shin, Ji Hyun, Kim, Yunha, Hwang, Jung Jin, Cho, Dong-Hyung, Kim, Jin Cheon
• Format: Article
• Language: English
• Subjects: Animals; ARP101; ATG5; Autophagy; Cancer cell; Cell death; Cell Line, Tumor; Humans; Matrix Metalloproteinase Inhibitors; Mice; Neoplasms - enzymology; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Small Molecule Libraries; Sulfonamides - chemistry; Sulfonamides - pharmacology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2010.12.106

► We screened the chemical libraries using a cell-based screening system and identified ARP101, a selective matrix metalloproteinase-2 inhibitor as a strong inducer of autophagy. ► Cell death induced by ARP101 was not inhibited by caspase inhibitor but by autophagy inhibitor. ► Our studies suggest that the selective MMP-2 inhibitor, ARP101, induces autophagy and autophagy-associated cell death. 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.