Dual functions of ARP101 in targeting membrane type ‐1 matrix metalloproteinase: Impact on U87 glioblastoma cell invasion and autophagy signaling

Membrane type ‐1 matrix (MT1‐MMP) metalloproteinase is highly expressed in glioblastoma. Inducing cancer cell autophagy may contribute to cancer therapy. We found that ARP101 exploits MT1‐MMP's signal transducing functions to trigger autophagy in a highly invasive glioblastoma cell line model. ARP101 may be envisioned in future therapy modalities against brain cancer. AbstractMembrane type ‐1 matrix metalloproteinase (MT1‐MMP) possesses both extracellular proteolytic and intracellular signal‐transducing functions in tumorigenesis. An imbalance in MT1‐MMP expression and/or function triggers a metastatic, invasive, and therapy resistance phenotype. MT1‐MMP is involved in extra cellular matrix (ECM) proteolysis, activation of latent MMPs, 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 AR P101 as a dual‐function small‐molecule inhibitor against MT1‐MMP ECM hydrolysis and autophagy signal‐transducing functions in a model of grade IV glioblastoma cells. ARP101 inhibited concanavalin‐A‐mediated proMMP‐2 activation into MMP‐2, as well as MT1‐MMP auto‐proteolytic proce ssing. When overexpressing recombinant Wt MT1‐MMP, ARP101 inhibited proMMP‐2 activation and triggered the formation of MT1‐MMP oligomers that required trafficking to the plasma membrane. ARP10...
Source: Chemical Biology and Drug Design - Category: Biology Authors: Tags: RESEARCH ARTICLE Source Type: research