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Dual functions of ARP 101 in targeting membrane type‐1 matrix metalloproteinase: Impact on U87 glioblastoma cell invasion and autophagy signaling
Author(s) -
Desjarlais Michel,
Annabi Borhane
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13410
Subject(s) - autophagy , microbiology and biotechnology , vacuole , gene silencing , chemistry , matrix metalloproteinase , signal transduction , biology , biochemistry , apoptosis , cytoplasm , gene
Membrane type‐1 matrix metalloproteinase ( MT 1‐ MMP ) possesses both extracellular proteolytic and intracellular signal‐transducing functions in tumorigenesis. An imbalance in MT 1‐ MMP expression and/or function triggers a metastatic, invasive, and therapy resistance phenotype. MT 1‐ MMP is involved in extracellular matrix ( ECM ) proteolysis, activation of latent MMP s, as well as in autophagy signaling in human hepatoma and glioblastoma cells. A low autophagy index in tumorigenesis has been inferred by recent studies where autophagic capacity was decreased during tumor progression. Here, we establish ARP 101 as a dual‐function small‐molecule inhibitor against MT 1‐ MMP ECM hydrolysis and autophagy signal‐transducing functions in a model of grade IV glioblastoma cells. ARP 101 inhibited concanavalin‐A‐mediated pro MMP ‐2 activation into MMP ‐2, as well as MT 1‐ MMP auto‐proteolytic processing. When overexpressing recombinant Wt MT 1‐ MMP , ARP 101 inhibited pro MMP ‐2 activation and triggered the formation of MT 1‐ MMP oligomers that required trafficking to the plasma membrane. ARP 101 further induced cell autophagy as reflected by increased formation of acidic vacuole organelles, LC 3 puncta, and autophagy‐related protein ATG 9 transcription. These were all significantly reversed upon si RNA ‐mediated gene silencing of MT 1‐ MMP . ARP 101 can thus concomitantly inhibit MT 1‐ MMP extracellular catalytic function and exploit its intracellular transducing signal function to trigger autophagy‐mediated cell death in U87 glioblastoma cancer cells.