TY - JOUR
T1 - Novel mechanism of apoptosis resistance in cancer mediated by extracellular PAR-4
AU - Burikhanov, Ravshan
AU - Shrestha-Bhattarai, Tripti
AU - Qiu, Shirley
AU - Shukla, Nidhi
AU - Hebbar, Nikhil
AU - Lele, Subodh M.
AU - Horbinski, Craig
AU - Rangnekar, Vivek M.
PY - 2013/1/15
Y1 - 2013/1/15
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84872509120&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-12-3212
DO - 10.1158/0008-5472.CAN-12-3212
M3 - Article
C2 - 23204231
AN - SCOPUS:84872509120
SN - 0008-5472
VL - 73
SP - 1011
EP - 1019
JO - Cancer Research
JF - Cancer Research
IS - 2
ER -