Novel mechanism of apoptosis resistance in cancer mediated by extracellular PAR-4

Ravshan Burikhanov, Tripti Shrestha-Bhattarai, Shirley Qiu, Nidhi Shukla, Nikhil Hebbar, Subodh M. Lele, Craig Horbinski, Vivek M. Rangnekar

Research output: Contribution to journalArticle

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1011-1019
Number of pages9
JournalCancer Research
Volume73
Issue number2
DOIs
StatePublished - Jan 15 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Burikhanov, R., Shrestha-Bhattarai, T., Qiu, S., Shukla, N., Hebbar, N., Lele, S. M., Horbinski, C., & Rangnekar, V. M. (2013). Novel mechanism of apoptosis resistance in cancer mediated by extracellular PAR-4. Cancer Research, 73(2), 1011-1019. https://doi.org/10.1158/0008-5472.CAN-12-3212