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

Chem Biol Drug Des. 2019 Mar;93(3):272-282. doi: 10.1111/cbdd.13410. Epub 2018 Oct 30.

Abstract

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.

Keywords: ARP101; MT1-MMP processing; autophagy; concanavalin-A; glioblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / drug effects*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Concanavalin A / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Matrix Metalloproteinase 14 / chemistry*
  • Matrix Metalloproteinase 14 / genetics
  • Matrix Metalloproteinase 14 / metabolism
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology*

Substances

  • ARP101 compound
  • RNA, Small Interfering
  • Sulfonamides
  • Concanavalin A
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 14