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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Low extracellular pH augments TRAIL-induced apoptotic death through the mitochondria-mediated caspase signal

Yong J Lee1, Jae J Song, Jin H Kim

  • 1Department of Surgery and Cancer Institute, School of Medicine, University of Pittsburgh, PA 15213, USA. leeyj@msx.upmc.edu

Experimental Cell Research
|January 20, 2004
PubMed

Insights

Low extracellular pH significantly enhances tumor necrosis factor-related apoptosis inducing ligand (TRAIL) cancer therapy effectiveness. This study reveals TRAIL-induced apoptosis is promoted in acidic tumor microenvironments, improving cancer cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising cancer therapeutic agent.
  • Solid tumor microenvironments, including low pH, can impact chemotherapy efficacy.
  • The relationship between tumor microenvironments and TRAIL effectiveness requires further investigation.

Purpose of the Study:

  • To investigate the effect of low extracellular pH on TRAIL-induced apoptotic cell death.
  • To elucidate the molecular mechanisms underlying pH-mediated TRAIL sensitivity.

Main Methods:

  • Treatment of human prostate carcinoma DU145 and colorectal carcinoma CX-1 cells with His-tagged TRAIL at varying pH levels.
  • Analysis of caspase activation, cytochrome c release, and PARP cleavage.
  • Immunoprecipitation and western blot analysis to assess protein interactions and expression levels.

Main Results:

  • TRAIL treatment resulted in significantly lower cell survival at acidic pH (6.3-6.6) compared to neutral pH (7.4).
  • Low extracellular pH promoted TRAIL-mediated caspase activation, cytochrome c release, and PARP cleavage.
  • Acidic pH enhanced the association of truncated Bid with Bax, a key step in apoptosis induction.
  • TRAIL receptor levels, FLIP, IAP, and Bcl-2 expression were not modulated by low pH.
  • Overexpression of Bcl-2 counteracted the enhanced TRAIL cytotoxicity at low pH.

Conclusions:

  • Low extracellular pH significantly enhances TRAIL-mediated cytotoxicity in cancer cells.
  • This enhancement is primarily mediated by promoting caspase activation through mechanisms involving Bid-Bax interaction.
  • TRAIL-based cancer therapies may be more effective in the acidic microenvironments of solid tumors.

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