The tumor suppressor protein Par-4, which is secreted by normal cells, selectively induces apoptosis in cancer cells. We identified a 3-arylquinoline derivative, designated Arylquin 1, as a potent Par-4 secretagogue in cell cultures and mice. Mechanistically, Arylquin 1 binds to vimentin, displaces Par-4 from vimentin for secretion and triggers the efficient paracrine apoptosis of diverse cancer cells. Thus, targeting vimentin with Par-4 secretagogues efficiently induces paracrine apoptosis of tumor cells.
Par-4 is a pro-apoptotic, tumor suppressor protein that induces apoptosis selectively in cancer cells. Endoplasmic reticulum-stress and higher levels of protein kinase A in tumor cells confer the coveted feature of cancer selective response to extracellular and intracellular Par-4, respectively. Recent studies have shown that systemic Par-4 confers resistance to tumor growth in mice, and that tumor-resistance is transferable by bone marrow transplantation. Moreover, recombinant Par-4 inhibits the growth of tumors in mice. As systemic Par-4 induces apoptosis via cell surface GRP78, strategies that promote GRP78 trafficking to the cell surface are expected sensitize cancer cells to circulating levels of Par-4. This review illustrates the domains and mechanisms by which Par-4 orchestrates the apoptotic process in both cell culture models and in physiological settings.
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 anti-apoptosis by NF-kappaB, revealing that it can block PAR-4-mediated apoptosis by downregulating trafficking of the PAR-4 receptor GRP78 from the endoplasmic reticulum (ER) to the cell surface. Mechanistic investigations revealed that NF-kappaB mediated this anti-apoptotic mechanism by upregulating expression of UACA, a pro-inflammatory protein in certain disease settings. In clinical specimens of cancer, a strong correlation existed between NF-kappaB 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 ER to the cell surface. This pathway of anti-apoptosis could be inhibited by suppressing levels of NF-kappaB or UACA expression, which enhanced ER 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-kappaB through UACA elevation, which by attenuating ER stress and GRP78 translocation to the cell surface can blunt the sensitivity of cancer cells to apoptosis.
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