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The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis

Ravshan Burikhanov1, Yanming Zhao, Anindya Goswami

  • 1Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536, USA.

Cell
|July 28, 2009
PubMed

Insights

Prostate apoptosis response-4 (Par-4) is secreted by cells and induces cancer cell apoptosis by binding to cell surface GRP78. This extracellular Par-4 signaling activates a death pathway, offering a potential therapeutic target.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Prostate apoptosis response-4 (Par-4) is a known intracellular proapoptotic protein.
  • Par-4 is unexpectedly found to be secreted by both normal and cancer cells.
  • Tumor resistance in Par-4 transgenic mice suggests a role for secreted Par-4.

Purpose of the Study:

  • To investigate the mechanism and function of extracellular Par-4 secretion.
  • To identify the receptor and pathway through which extracellular Par-4 induces apoptosis.
  • To explore the role of extracellular Par-4 in TRAIL-induced apoptosis.

Main Methods:

  • Cell culture and treatment with ER stress-inducing agents.
  • Analysis of Par-4 secretion pathways (brefeldin A sensitivity).
  • Investigating extracellular Par-4 interaction with cell surface proteins (GRP78) and downstream signaling (FADD/caspase pathway).

Main Results:

  • Par-4 is spontaneously secreted by cells and its secretion is enhanced by ER stress via a brefeldin A-sensitive pathway.
  • Extracellular Par-4 induces apoptosis in cancer cells by binding to cell surface GRP78.
  • This interaction triggers ER stress and activates the FADD/caspase-8/caspase-3 apoptotic pathway.
  • TRAIL-induced apoptosis is dependent on extracellular Par-4 signaling through cell surface GRP78.

Conclusions:

  • Extracellular Par-4 acts as a signaling molecule to induce cancer cell-specific apoptosis.
  • The Par-4/cell surface GRP78 interaction represents a novel extrinsic apoptotic pathway.
  • This pathway offers a potential therapeutic strategy for cancer treatment.

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