title: ARP101, a selective MMP-2 inhibitor, induces autophagy-associated cell death in cancer cells.
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.
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Jo
authors.forename: So Jung
authors.initials: SJ
authors.lastname: Park
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Shin
authors.forename: Yunha
authors.initials: Y
authors.lastname: Kim
authors.forename: Jung Jin
authors.initials: JJ
authors.lastname: Hwang
authors.forename: Dong-Hyung
authors.initials: DH
authors.lastname: Cho
authors.forename: Jin Cheon
authors.initials: JC
authors.lastname: Kim
mesh_terms: D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D009369:Neoplasms / Q000201:enzymology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C556450:ARP101 compound; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D013449:Sulfonamides