Novel Mechanism of Apoptosis Resistance in Cancer Mediated by Extracellular PAR-4

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-01, Vol.73 (2), p.1011-1019
• Main Authors: BURIKHANOV, Ravshan, SHRESTHA-BHATTARAI, Tripti, QIU, Shirley, SHUKLA, Nidhi, HEBBAR, Nikhil, LELE, Subodh M, HORBINSKI, Craig, RANGNEKAR, Vivek M
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Apoptosis; Apoptosis Regulatory Proteins - metabolism; Autoantigens - metabolism; Biological and medical sciences; Cell Line, Tumor; Cell Membrane - metabolism; Cell Survival; Endoplasmic Reticulum - metabolism; Extracellular Space - metabolism; Heat-Shock Proteins - metabolism; Humans; Medical sciences; Neoplasms - metabolism; NF-kappa B - metabolism; Pharmacology. Drug treatments; Protein Transport; Receptors, Proteinase-Activated - metabolism; Signal Transduction; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-12-3212

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.