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
Summary
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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