The Tumor Suppressor Par-4 Activates an Extrinsic Pathway for Apoptosis

Ravshan Burikhanov, Yanming Zhao, Anindya Goswami, Shirley Qiu, Steven R. Schwarze, Vivek M. Rangnekar

Research output: Contribution to journalArticlepeer-review

179 Scopus citations

Abstract

Prostate apoptosis response-4 (Par-4) is a proapoptotic protein with intracellular functions in the cytoplasm and nucleus. Unexpectedly, we noted Par-4 protein is spontaneously secreted by normal and cancer cells in culture, and by Par-4 transgenic mice that are resistant to spontaneous tumors. Short exposure to endoplasmic reticulum (ER) stress-inducing agents further increased cellular secretion of Par-4 by a brefeldin A-sensitive pathway. Secretion occurred independently of caspase activation and apoptosis. Interestingly, extracellular Par-4 induced apoptosis by binding to the stress response protein, glucose-regulated protein-78 (GRP78), expressed at the surface of cancer cells. The interaction of extracellular Par-4 and cell surface GRP78 led to apoptosis via ER stress and activation of the FADD/caspase-8/caspase-3 pathway. Moreover, apoptosis inducible by TRAIL, which also exerts cancer cell-specific effects, is dependent on extracellular Par-4 signaling via cell surface GRP78. Thus, Par-4 activates an extrinsic pathway involving cell surface GRP78 receptor for induction of apoptosis.

Original languageEnglish
Pages (from-to)377-388
Number of pages12
JournalCell
Volume138
Issue number2
DOIs
StatePublished - Jul 23 2009

Bibliographical note

Funding Information:
This study was supported by NIH/NCI grants CA60872, CA105453, and CA84511 (to V.M.R.). We thank Krishna Murthi Vasudevan (Dana-Farber Cancer Institute) for critical reading of the manuscript.

Keywords

  • CELLBIO
  • HUMDISEASE
  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)

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