Dual functions of ARP101 in targeting membrane type‐1 matrix metalloproteinase: Impact on U87 glioblastoma cell invasion and autophagy signaling
Membrane 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 ex...
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Published in | Chemical biology & drug design Vol. 93; no. 3; pp. 272 - 282 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
England
01.03.2019
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Subjects | |
Online Access | Get full text |
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Summary: | Membrane 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 extracellular 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 ARP101 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 processing. 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. ARP101 further induced cell autophagy as reflected by increased formation of acidic vacuole organelles, LC3 puncta, and autophagy‐related protein ATG9 transcription. These were all significantly reversed upon siRNA‐mediated gene silencing of MT1‐MMP. ARP101 can thus concomitantly inhibit MT1‐MMP extracellular catalytic function and exploit its intracellular transducing signal function to trigger autophagy‐mediated cell death in U87 glioblastoma cancer cells.
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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1747-0277 1747-0285 |
DOI: | 10.1111/cbdd.13410 |