Systemic Par-4 inhibits non-autochthonous tumor growth. Cancer Biol Ther

Department of Radiation Medicine, University of Kentucky, Lexington, KY USA.
Cancer biology & therapy (Impact Factor: 3.07). 07/2011; 12(2):152-7. DOI: 10.4161/cbt.12.2.15734
Source: PubMed


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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Available from: Ravshan Burikhanov, Jan 12, 2015
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    • "In summary, our findings suggest that the tumor suppressor p53 regulates the secretion of the proapoptotic, tumor suppressor Par-4 via the classical pathway by suppressing UACA, and that Par-4 executes the paracrine apoptotic effects of p53. As systemic Par-4 inhibits the growth of lung tumors (Zhao et al., 2011), Par-4 secretagogues can be exploited to activate p53 and unleash the power of normal cells in the tumor microand macroenvironment to elevate systemic Par-4 and suppress tumor cell survival. "
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    ABSTRACT: The guardian of the genome, p53, is often mutated in cancer and may contribute to therapeutic resistance. Given that p53 is intact and functional in normal tissues, we harnessed its potential to inhibit the growth of p53-deficient cancer cells. Specific activation of p53 in normal fibroblasts selectively induced apoptosis in p53-deficient cancer cells. This paracrine effect was mediated by p53-dependent secretion of the tumor suppressor Par-4. Accordingly, the activation of p53 in normal mice, but not p53(-)/(-) or Par-4(-)/(-) mice, caused systemic elevation of Par-4, which induced apoptosis of p53-deficient tumor cells. Mechanistically, p53 induced Par-4 secretion by suppressing the expression of its binding partner, UACA, which sequesters Par-4. Thus, normal cells can be empowered by p53 activation to induce Par-4 secretion for the inhibition of therapy-resistant tumors.
    Cell Reports 01/2014; 6(2). DOI:10.1016/j.celrep.2013.12.020 · 8.36 Impact Factor
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    • "Recently, it was observed that Par-4 protein is also spontaneously secreted by normal and cancer cells to the extracellular compartment (cell culture-conditioned medium or circulating in serum) and is able to induce cancer cell-specific apoptosis by interacting with the cell-surface receptor GRP78 and activating the FADD/caspase-8/caspase-3 pathway (19). Moreover, transgenic mice that express systemic Par-4 protein are resistant to the growth of non-autochthonous tumors and intravenous injection of recombinant Par-4 inhibits metastasis (20). In cholangiocarcinoma cells, cell proliferation is associated with reduced Par-4 expression as cells selectively silenced for Par-4 demonstrated a significant increase in cell proliferation and reduced apoptosis (21). "
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    ABSTRACT: Experimental evidence indicates that prostate apoptosis response-4 (Par-4, also known as PAWR) is a key regulator of cancer cell survival and may be a target for cancer-selective targeted therapeutics. Par-4 was first identified in prostate cancer cells undergoing apoptosis. Both intracellular and extracellular Par-4 have been implicated in apoptosis. Relatively little is known about the role of Par-4 in breast cancer cell apoptosis. In this study, we sought to investigate the effects of Par-4 expression on cell proliferation, apoptosis and drug sensitivity in breast cancer cells. MCF-7 cells were stably transfected with expression vectors for Par-4, or transiently transfected with siRNA for Par-4 knockdown. Cell proliferation assays were performed using MTT and apoptosis was evaluated using acridine orange staining, fluorescence microscopy and flow cytometry. Par-4 overexpression reduced MCF-7 proliferation rates. Conversely, Par-4 knockdown led to increased MCF-7 proliferation. Par-4 downregulation also led to increased BCL-2 and reduced BID expression. Par-4 overexpression did not affect the cell cycle profile. However, MCF-7 cells with increased Par-4 expression showed reduced ERK phosphorylation, suggesting that the inhibition of cell proliferation promoted by Par-4 may be mediated by the MAPK/ERK1/2 pathway. MCF-7 cells with increased Par-4 expression showed a marginal increase in early apoptotic cells. Importantly, we found that Par-4 expression modulates apoptosis in response to docetaxel in MCF7 breast cancer cells. Par-4 exerts growth inhibitory effects on breast cancer cells and chemosensitizes them to docetaxel.
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