The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis.
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.
Burikhanov
Ravshan
R
Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536, USA.
Zhao
Yanming
Y
Goswami
Anindya
A
Qiu
Shirley
S
Schwarze
Steven R
SR
Rangnekar
Vivek M
VM
D000818:Animals; D017209:Apoptosis; D020126:Brefeldin A / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D018179:Receptors, Thrombin / Q000737:chemistry / Q000378:metabolism*
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018179:Receptors, Thrombin; D020126:Brefeldin A; C112908:protease-activated receptor 4