title: Novel mechanism of apoptosis resistance in cancer mediated by extracellular PAR-4.
abstract: Tumor suppressor PAR-4 acts in part by modulating sensitivity to apoptosis, but the basis for its activity is not fully understood. In this study, we describe a novel mechanism of antiapoptosis by NF-κB, revealing that it can block PAR-4-mediated apoptosis by downregulating trafficking of the PAR-4 receptor GRP78 from the endoplasmic reticulum to the cell surface. Mechanistic investigations revealed that NF-κB mediated this antiapoptotic mechanism by upregulating expression of UACA, a proinflammatory protein in certain disease settings. In clinical specimens of cancer, a strong correlation existed between NF-κB activity and UACA expression, relative to normal tissues. UACA bound to intracellular PAR-4 in diverse cancer cells, where it prevented translocation of GRP78 from the endoplasmic reticulum to the cell surface. This pathway of antiapoptosis could be inhibited by suppressing levels of NF-κB or UACA expression, which enhanced endoplasmic reticulum stress and restored GRP78 trafficking to the cell surface, thereby sensitizing cancer cells to apoptosis by extracellular PAR-4 or GRP78 agonistic antibody. In summary, our results identify a novel intracellular pathway of apoptosis mediated by NF-κB through UACA elevation, which by attenuating endoplasmic reticulum stress and GRP78 translocation to the cell surface can blunt the sensitivity of cancer cells to apoptosis.
authors.affiliation: Department of Radiation Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Ravshan
authors.initials: R
authors.lastname: Burikhanov
authors.forename: Tripti
authors.initials: T
authors.lastname: Shrestha-Bhattarai
authors.forename: Shirley
authors.initials: S
authors.lastname: Qiu
authors.forename: Nidhi
authors.initials: N
authors.lastname: Shukla
authors.forename: Nikhil
authors.initials: N
authors.lastname: Hebbar
authors.forename: Subodh M
authors.initials: SM
authors.lastname: Lele
authors.forename: Craig
authors.initials: C
authors.lastname: Horbinski
authors.forename: Vivek M
authors.initials: VM
authors.lastname: Rangnekar
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001324:Autoantigens / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005110:Extracellular Space / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D021381:Protein Transport; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D016328:NF-kappa B; D044462:Receptors, Proteinase-Activated; C422446:UACA antigen; C101296:prostate apoptosis response-4 protein; C481942:protease-activated receptor 4, mouse