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ARP101, a selective MMP-2 inhibitor, induces autophagy-associated cell death in cancer cells

Yoon Kyung Jo1, So Jung Park, Ji Hyun Shin

  • 1Institute for Innovative Cancer Research, Asan Medical Center, Seoul 138-736, Republic of Korea.

Biochemical and Biophysical Research Communications
|December 29, 2010
PubMed

Insights

A selective matrix metalloproteinase-2 (MMP-2) inhibitor, ARP101, potently induces autophagy, a cellular self-digestion process. This autophagy induction by ARP101 is linked to significant cell death, highlighting a novel therapeutic avenue.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Autophagy is a fundamental cellular process for macromolecule and organelle turnover, crucial for cellular stress response.
  • While often protective, autophagy can be implicated in cell death pathways and acts as a tumor suppressor mechanism.
  • Identifying specific regulators of autophagy is key to understanding its diverse roles.

Purpose of the Study:

  • To identify novel chemical regulators that modulate autophagy.
  • To investigate the mechanism by which identified compounds induce autophagy.
  • To determine the role of autophagy in ARP101-induced cell death.

Main Methods:

  • Screening of chemical libraries (Lopac 1280, Prestwick) using a GFP-LC3 autophagy marker system.
  • Treatment of cells with ARP101 and assessment of autophagosome formation and LC3 conversion (LC3I to LC3II).
  • Utilizing ATG5(-/-) MEF cells to confirm autophagy-dependent effects and employing 3-methyladenine and zVAD to dissect cell death pathways.

Main Results:

  • ARP101 was identified as a potent inducer of autophagy, significantly increasing autophagosome formation and LC3II levels.
  • ARP101-induced autophagy was dependent on ATG5, confirming its role in the autophagic pathway.
  • Cell death induced by ARP101 was mediated by autophagy, as it was blocked by autophagy inhibitors but not by caspase inhibitors.

Conclusions:

  • ARP101, a selective MMP-2 inhibitor, is a potent inducer of autophagy.
  • The study demonstrates that ARP101-induced cell death is associated with and dependent on autophagy.
  • These findings suggest ARP101 as a potential therapeutic agent targeting pathways involving autophagy and cell death.

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