The Tumor Suppressor Par-4 Activates an Extrinsic Pathway for Apoptosis

Burikhanov, Ravshan; Zhao, Yanming; Goswami, Anindya; Qiu, Shirley; Schwarze, Steven R.

doi:10.1016/j.cell.2009.08.015

Cited by 58 publications

(101 citation statements)

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“…Extracellular Par-4 binds to cell-surface GRP78 and induces apoptosis via TRAIL. 7 Although K5 was hypothesized to be internalized into ECs, no experimental evidence has been presented. 6 We demonstrated here that ISM is efficiently internalized into ECs through clathrin-dependent endocytosis and internalization is essential for its antiangiogenic and proapoptotic function (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

“…Although intracellular GRP78 is known for its pro-survival and anti-apoptotic function, cell-surface GRP78 serves as a receptor for proapoptotic ligands such as Kringle-5 (K5) and Par-4, thereby promoting apoptosis. 6,7 As cell-surface GRP78 is preferentially present in cancer cells, it is an attractive target for cancer therapy. [8][9][10] Indeed, synthetic peptides containing cell-surface GRP78-binding motifs conjugated to proapoptotic peptide suppressed primary tumor growth as well as established micrometastasis in mice.…”

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confidence: 99%

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Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Zhang

et al. 2014

Cell Death Differ

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Isthmin (ISM) is a secreted 60-kDa protein that potently induces endothelial cell (EC) apoptosis. It suppresses tumor growth and angiogenesis in mice when stably overexpressed in cancer cells. Although avb5 integrin serves as a low-affinity receptor for ISM, the mechanism by which ISM mediates antiangiogenesis and apoptosis in ECs remain to be fully resolved. In this work, we report the identification of cell-surface glucose-regulated protein 78 kDa (GRP78) as a high-affinity receptor for ISM (K d ¼ 8.6 nM). We demonstrated that ISM-GRP78 interaction triggers apoptosis not only in activated ECs but also in cancer cells expressing high level of cell-surface GRP78. Normal cells and benign tumor cells tend to express low level of cell-surface GRP78 and are resistant to ISM-induced apoptosis. Upon binding to GRP78, ISM is internalized into ECs through clathrin-dependent endocytosis that is essential for its proapoptotic activity. Once inside the cell, ISM co-targets with GRP78 to mitochondria where it interacts with ADP/ATP carriers on the inner membrane and blocks ATP transport from mitochondria to cytosol, thereby causing apoptosis. Hence, ISM is a novel proapoptotic ligand that targets cell-surface GRP78 to trigger apoptosis by inducing mitochondrial dysfunction. The restricted and high-level expression of cell-surface GRP78 on cancer cells and cancer ECs make them uniquely susceptible to ISM-targeted apoptosis. Indeed, systemic delivery of recombinant ISM potently suppressed subcutaneous 4T1 breast carcinoma and B16 melanoma growth in mice by eliciting apoptosis selectively in the cancer cells and cancer ECs. Together, this work reveals a novel ISM-GRP78 apoptosis pathway and demonstrates the potential of ISM as a cancer-specific and dual-targeting anticancer agent.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Zhang

et al. 2014

Cell Death Differ

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“…The level of PAR-4 protein expression was significantly higher in MCF-7 cells compared with MDA-MB-231 cells. PAR-4 has been classified as a tumor suppressor gene with pro-apoptotic activity that has a function in both ligand-mediated extrinsic and mitochondrial mediated intrinsic apoptosis [15,20]. In normal or immortalized cells, PAR-4 expression is not sufficient to induce apoptosis, but it increases cellular sensitivity to several apoptotic stimuli [21].…”

Section: Resultsmentioning

confidence: 99%

“…Experimental evidence indicates that PAWR (PKC apoptosis WT1 regulator; also named PAR-4, prostate apoptosis response-4) is one of the central players in cancer cell survival and could be a target for cancer-selective targeted therapeutics [12]. The PAR-4 protein is ubiquitously expressed and localized in the cytoplasm of diverse normal tissues and cell lines, in both the cytoplasm and nucleus of many tumors and cancer cells, and very recently has been shown to be secreted [13][14][15]. Expression of PAR-4 may increase most cancer cell's sensitivity to apoptosis, especially in hormone-independent cancer cell lines, including breast cancer cells [14].…”

Section: Introductionmentioning

confidence: 99%

Expression Pattern of the Pro-apoptotic Gene PAR-4 During the Morphogenesis of MCF-10A Human Mammary Epithelial Cells

Garcia

Pereira

Nagai

2010

Cancer Microenvironment

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The histological organization of the mammary gland involves a spatial interaction of epithelial and myoepithelial cells with the specialized basement membrane (BM), composed of extra-cellular matrix (ECM) proteins, which is disrupted during the tumorigenic process. The interactions between mammary epithelial cells and ECM components play a major role in mammary gland branching morphogenesis. Critical signals for mammary epithelial cell proliferation, differentiation, and survival are provided by the ECM proteins. Three-dimensional (3D) cell culture was developed to establish a system that simulates several features of the breast epithelium in vivo; 3D cell culture of the spontaneously immortalized cell line, MCF10A, is a well-established model system to study breast epithelial cell biology and morphogenesis. Mammary epithelial cells grown in 3D form spheroids, acquire apicobasal polarization, and form lumens that resemble acini structures, processes that involve cell death. Using this system, we evaluated the expression of the proapoptotic gene PAWR (PKC apoptosis WT1 regulator; also named PAR-4, prostate apoptosis response-4) by immunofluorescence and quantitative real time PCR (qPCR). A time-dependent increase in PAR-4 mRNA expression was found during the process of MCF10A acinar morphogenesis. Confocal microscopy analysis also showed that PAR-4 protein was highly expressed in the MCF10A cells inside the acini structure. During the morphogenesis of MCF10A cells in 3D cell culture, the cells within the lumen showed caspase-3 activation, indicating apoptotic activity. PAR-4 was only partially co-expressed with activated caspase-3 on these cells. Our results provide evidence, for the first time, that PAR-4 is differentially expressed during the process of MCF10A acinar morphogenesis.

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“…the Par-4 protein is ubiquitously expressed and is localized in the cytoplasm of diverse normal tissues and cell lines, as well as in both the cytoplasm and the nucleus of many tumors and cancer cells (5)(6)(7). a recent study provides evidence that Par-4 is also secreted by cells, and therefore is also present in the extracellular compartment (cell culture conditioned medium or circulating in serum) (8). its expression sensitizes numerous cell types to apoptosis in response to diverse apoptotic stimuli (such as intracellular calcium elevation, tnfα, doxorubicin, or growth factor withdrawal), but is not sufficient to induce apoptotic cell death (6,9).…”

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor-1 and 17β-estradiol down-regulate prostate apoptosis response-4 expression in MCF-7 breast cancer cells

Casolari

Pereira²,

Garcia³

et al. 2011

Int J Mol Med

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Abstract. the PKc apoptosis Wt1 regulator gene, also named prostate apoptosis response-4 (Par-4), encodes a pro-apoptotic protein that sensitizes cells to numerous apoptotic stimuli. insulin-like growth factor-1 (iGf-1) and 17β-estradiol (e2), two important factors for breast cancer development and progression, have been shown to downregulate Par-4 expression and inhibit apoptosis induced by Par-4 in neuronal cells. in this study, we sought to investigate the mechanisms of regulation of Par-4 gene expression in mcf-7 cells treated with e2 or iGf-1. e2 (10 nm) and iGf-1 (12.5 nm) each down-regulated Par-4 expression in mcf-7 cells after 24 h of treatment. the effect of e2 was dependent on er activation, as demonstrated by an increase in Par-4 expression when cells were pretreated for 1 h with 1 µm ici-182,780 (ici) before receiving e2 plus ici. the effect of iGf-1 was abolished by pre-treatment for 1 h with 30 µm lY294002 (a specific Pi3-K inhibitor), and significantly inhibited by 30 µM SB202190 (a specific p38MAPK inhibitor). We also demonstrated that e2 acts synergistically with iGf-1, resulting in greater down-regulation of Par-4 mrna expression compared with e2 or iGf-1 alone. our results show for the first time that E2 and IGF-1 inhibit PAR-4 gene expression in mcf-7 cells, suggesting that this down-regulation may provide a selective advantage for breast cancer cell survival.

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The Tumor Suppressor Par-4 Activates an Extrinsic Pathway for Apoptosis

Cited by 58 publications

References 0 publications

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Expression Pattern of the Pro-apoptotic Gene PAR-4 During the Morphogenesis of MCF-10A Human Mammary Epithelial Cells

Insulin-like growth factor-1 and 17β-estradiol down-regulate prostate apoptosis response-4 expression in MCF-7 breast cancer cells

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