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Protease-activated receptor-1 impedes prostate and intestinal tumor progression in mice.

ABSTRACT: Essentials Protease activated receptor-1 (PAR-1) has been proposed to drive cancer progression. Surprisingly, PAR-1 deletion accelerated tumor progression in two distinct experimental settings. PAR-1 deletion was shown to limit the apoptosis of transformed epithelial cells. Thrombin- and activated protein C-mediated PAR-1 activation have unique effects on tumor cell biology. SUMMARY: Background Multiple studies have implicated protease-activated receptor-1 (PAR-1), a G-protein-coupled receptor activated by proteolytic cleavage of its N-terminus, as one target coupling thrombin-mediated proteolysis to tumor progression. Objective To analyze the role of PAR-1 in the setting of two distinct spontaneously developing tumor models in mice. Methods We interbred PAR-1-deficient mice with Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, which spontaneously develop prostate tumors, and adenomatous polyposis coli Min (APCM in/+ ) mice, which spontaneously develop intestinal adenomas. Results Analyses of TRAMP mice with advanced disease (30 weeks) revealed that PAR-1 deficiency resulted in significantly larger and more aggressive prostate tumors. Prostates collected at an earlier time point (12 weeks of age) revealed that PAR-1 promotes apoptosis in transformed epithelia. In vitro analyses of TRAMP-derived cells revealed that activated protein C-mediated PAR-1 cleavage can induce tumor cell apoptosis, suggesting that tumor cell-intrinsic PAR-1 functions can limit tumor progression. Paralleling results in TRAMP mice, PAR-1-deficient APCM in/+ mice developed three-fold more adenomas than PAR-1-expressing mice, and the adenomas that formed were significantly larger. Moreover, loss of PAR-1 expression was shown to limit apoptosis in transformed intestinal epithelial cells. Conclusions Together, these results demonstrate a previously unrecognized role for PAR-1 in impeding tumor progression in vivo. These results also offer a cautionary note suggesting that long-term PAR-1 inhibition could increase malignancy risk in some contexts.

SUBMITTER: Adams GN

PROVIDER: S-EPMC6214773 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Protease-activated receptor-1 impedes prostate and intestinal tumor progression in mice.

Adams G N GN Sharma B K BK Rosenfeldt L L Frederick M M Flick M J MJ Witte D P DP Mosnier L O LO Harmel-Laws E E Steinbrecher K A KA Palumbo J S JS

Journal of thrombosis and haemostasis : JTH 20180927 11

Essentials Protease activated receptor-1 (PAR-1) has been proposed to drive cancer progression. Surprisingly, PAR-1 deletion accelerated tumor progression in two distinct experimental settings. PAR-1 deletion was shown to limit the apoptosis of transformed epithelial cells. Thrombin- and activated protein C-mediated PAR-1 activation have unique effects on tumor cell biology. SUMMARY: Background Multiple studies have implicated protease-activated receptor-1 (PAR-1), a G-protein-coupled receptor a ...[more]

PMID: 30152921

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Project description:Malignant gliomas can be counted to the most devastating tumors in humans. Novel therapies do not achieve significant prolonged survival rates. The cancer cells have an impact on the surrounding vital tissue and form tumor zones, which make up the tumor microenvironment. We investigated the effects of sunitinib, a small molecule multitargeted receptor tyrosine kinase inhibitor, on constituents of the tumor microenvironment such as gliomas, astrocytes, endothelial cells, and neurons. Sunitinib has a known anti-angiogenic effect. We found that sunitinib normalizes the aberrant tumor-derived vasculature and reduces tumor vessel pathologies (i.e. auto-loops). Sunitinib has only minor effects on the normal, physiological, non-proliferating vasculature. We found that neurons and astrocytes are protected by sunitinib against glutamate-induced cell death, whereas sunitinib acts as a toxin towards proliferating endothelial cells and tumor vessels. Moreover, sunitinib is effective in inducing glioma cell death. We determined the underlying pathways by which sunitinib operates as a toxin on gliomas and found vascular endothelial growth factor receptor 2 (VEGFR2, KDR/Flk1) as the main target to execute gliomatoxicity. The apoptosis-inducing effect of sunitinib can be mimicked by inhibition of VEGFR2. Knockdown of VEGFR2 can, in part, foster the resistance of glioma cells to receptor tyrosine kinase inhibitors. Furthermore, sunitinib alleviates tumor-induced neurodegeneration. Hence, we tested whether temozolomide treatment could be potentiated by sunitinib application. Here we show that sunitinib can amplify the effects of temozolomide in glioma cells. Thus, our data indicate that combined treatment with temozolomide does not abrogate the effects of sunitinib. In conclusion, we found that sunitinib acts as a gliomatoxic agent and at the same time carries out neuroprotective effects, reducing tumor-induced neurodegeneration. Thus, this report uncovered sunitinib's actions on the brain tumor microenvironment, revealing novel aspects for adjuvant approaches and new clinical assessment criteria when applied to brain tumor patients.

Project description:BACKGROUND:Pain is the most debilitating symptom of migraine. The cause of migraine pain likely requires activation of meningeal nociceptors. Mast cell degranulation, with subsequent meningeal nociceptor activation, has been implicated in migraine pathophysiology. Degranulating mast cells release serine proteases that can cleave and activate protease activated receptors. The purpose of these studies was to investigate whether protease activated receptor 2 is a potential generator of nociceptive input from the meninges by using selective pharmacological agents and knockout mice. METHODS:Ratiometric Ca++ imaging was performed on primary trigeminal and dural cell cultures after application of 2at-LIGRL-NH2, a specific protease activated receptor 2 agonist. Cutaneous hypersensitivity and facial grimace was measured in wild-type and protease activated receptor 2-/- mice after dural application of 2at-LIGRL-NH2 or compound 48-80, a mast cell degranulator. Behavioral experiments were also conducted in mice after dural application of 2at-LIGRL-NH2 (2AT) in the presence of either C391, a selective protease activated receptor 2 antagonist, or sumatriptan. RESULTS:2at-LIGRL-NH2 evoked Ca2+ signaling in mouse trigeminal neurons, dural fibroblasts and in meningeal afferents. Dural application of 2at-LIGRL-NH2 or 48-80 caused dose-dependent grimace behavior and mechanical allodynia that were attenuated by either local or systemic application of C391 as well as in protease activated receptor 2-/- mice. Nociceptive behavior after dural injection of 2at-LIGRL-NH2 was also attenuated by sumatriptan. CONCLUSIONS:Functional protease activated receptor 2 receptors are expressed on both dural afferents and fibroblasts and activation of dural protease activated receptor 2 produces migraine-like behavioral responses. Protease activated receptor 2 may link resident immune cells to meningeal nociceptor activation, driving migraine-like pain and implicating protease activated receptor 2 as a therapeutic target for migraine in humans.

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Protease-activated receptor-1 impedes prostate and intestinal tumor progression in mice.

Publications

Protease-activated receptor-1 impedes prostate and intestinal tumor progression in mice.

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