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

Cell. 2009 Jul 23;138(2):377-88. doi: 10.1016/j.cell.2009.05.022.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis*
  • Brefeldin A / pharmacology
  • Cell Line
  • Cell Line, Tumor
  • Endoplasmic Reticulum / metabolism
  • Heat-Shock Proteins / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • Protein Structure, Tertiary
  • Protein Transport / drug effects
  • Receptors, Thrombin / chemistry
  • Receptors, Thrombin / metabolism*

Substances

  • Heat-Shock Proteins
  • Receptors, Thrombin
  • Brefeldin A
  • protease-activated receptor 4
  • molecular chaperone GRP78