Systemic Par-4 inhibits non-autochthonous tumor growth.

Department of Radiation Medicine, University of Kentucky, Lexington, KY USA.
Cancer biology & therapy (Impact Factor: 3.63). 07/2011; 12(2):152-7. DOI: 10.4161/cbt.12.2.15734
Source: PubMed

ABSTRACT The tumor suppressor protein Par-4 (Prostate apoptosis response-4) is spontaneously secreted by normal and cancer cells. Extracellular Par-4 induces caspase-dependent apoptosis in cancer cell cultures by binding, via its effector SAC domain, to cell surface GRP78 receptor. However, the functional significance of extracellular Par-4/SAC has not been validated in animal models. We show that Par-4/SAC-transgenic mice express systemic Par-4/SAC protein and are resistant to the growth of non-autochthonous tumors. Consistently, secretory Par-4/SAC pro-apoptotic activity can be transferred from these cancer-resistant transgenic mice to cancer-susceptible mice by bone marrow transplantation. Moreover, intravenous injection of recombinant Par-4 or SAC protein inhibits metastasis of cancer cells. Collectively, our findings indicate that extracellular Par-4/SAC is systemically functional in inhibition of tumor growth and metastasis progression, and may merit investigation as a therapy.

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    ABSTRACT: Introduction: Apoptosis plays an important role in age-related disease, and prostate apoptosis response-4 (PAR-4) is a novel apoptosis-inducing factor that regulates apoptosis in most cells. Recent studies suggest that PAR-4 plays an important role in the progression of many age-related diseases. This review highlights the significance of PAR-4 and builds a strong case supporting its role as a possible therapeutic target in age-related disease. Areas covered: This review covers the advancements over the last 15 years with respect to PAR-4 and its significance in age-related disease. Additionally, it provides knowledge regarding the significance of PAR-4 in age-related disease as well as its role in apoptotic signaling pathways, endoplasmic reticulum (ER) stress, and other mechanisms that may induce age-related disease. Expert Opinion: PAR-4 may be a potential therapeutic target that can trigger selective apoptosis in cancer cells. It is induced by ER stress and increased ER stress, and it is involved in the activity of the dopamine D2 receptor. Abnormal expression of PAR-4 may be associated with cardiovascular disease and diabetes. PAR-4 agonists and inhibitors must be identified before gene therapy can commence.
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    ABSTRACT: Prostate apoptosis response-4 (Par-4) is an endogenous tumor suppressor that selectively induces apoptosis in a variety of cancers. Although it has been the subject of intensive research in other cancers, less is known about its significance in gliomas, including whether it is regulated by key driver mutations, has therapeutic potential against glioma stem cells (GSCs), and/or is a prognostic marker. We found that patient-derived gliomas with mutant isocitrate dehydrogenase 1 have markedly lower Par-4 expression (P < 0.0001), which was validated by The Cancer Genome Atlas dataset (P = 2.0 E-13). The metabolic product of mutant IDH1, D-2-hydroxyglutarate (2-HG), can suppress Par-4 transcription in vitro via inhibition of promoter activity as well as enhanced mRNA degradation, but interestingly not by direct DNA promoter hypermethylation. The Selective for Apoptosis induction in Cancer cells (SAC) domain within Par-4 is highly active against glioma cells, including orthotopic xenografts of patient-derived primary GSCs (P < 0.0001). Among high-grade gliomas that are IDH1 wild type, those that express more Par-4 have significantly longer median survival (18.4 vs. 8.0 months, P = 0.002), a finding confirmed in two external GBM cohorts. Together, these data suggest that Par-4 is a significant component of the mutant IDH1 phenotype, that the activity of 2-HG is complex and can extend beyond direct DNA hypermethylation, and that Par-4 is a promising therapeutic strategy against GSCs. Furthermore, not every effect of mutant IDH1 necessarily contributes to the overall favorable prognosis seen in such tumors; inhibition of Par-4 may be one such effect.
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    ABSTRACT: The proapoptotic protein, prostate apoptosis response-4 (Par-4), acts as a tumor suppressor in prostate cancer cells. The serine/threonine kinase casein kinase 2 (CK2) has a well-reported role in prostate cancer resistance to apoptotic agents or anticancer drugs. However, the mechanistic understanding on how CK2 supports survival is far from complete. In this work, we demonstrate both in rat and humans that (i) Par-4 is a new substrate of the survival kinase CK2 and (ii) phosphorylation by CK2 impairs Par-4 proapoptotic functions. We also unravel different levels of CK2-dependent regulation of Par-4 between species. In rats, the phosphorylation by CK2 at the major site, S124, prevents caspase-mediated Par-4 cleavage (D123) and consequently impairs the proapoptotic function of Par-4. In humans, CK2 strongly impairs the apoptotic properties of Par-4, independently of the caspase-mediated cleavage of Par-4 (D131), by triggering the phosphorylation at residue S231. Furthermore, we show that human Par-4 residue S231 is highly phosphorylated in prostate cancer cells as compared with their normal counterparts. Finally, the sensitivity of prostate cancer cells to apoptosis by CK2 knockdown is significantly reversed by parallel knockdown of Par-4. Thus, Par-4 seems a critical target of CK2 that could be exploited for the development of new anticancer drugs.
    Cell Death & Disease 01/2014; 5(1):e1016. DOI:10.1038/cddis.2013.532 · 5.18 Impact Factor

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