Abstract 49: Interaction of the protein kinase C-related kinases with the TPα and TPβ isoforms of the T prostanoid receptor: role in thromboxane-induced neoplastic responses

Abstract

Abstract Compelling epidemiological evidence concurs that long-term use of aspirin lowers the risk of many prevalent cancers. While such studies do not specify which cyclooxygenase-1/2 metabolite(s) are lowered by aspirin accounting for its prophylactic benefits, many reports show that some of its anti-cancer effects are due to its ability to inhibit thromboxane (TX)A2 generation, a substance more typically known for its role in hemostasis/thrombosis. In humans, TXA2 signals through the TPα and TPβ isoforms of the T prostanoid receptor (TP). There is increasing evidence supporting roles for the TXA2 axis in several neoplasms including prostate cancer, potentially due to the ability of TPα/TPβ to regulate key RhoA- and ERK-mediated signalling cascades that contribute to tumor growth & metastasis. Mechanistically, we recently identified protein kinase C-related kinase (PRK) 1 as a direct interacting partner of TPα/TPβ, a functional interaction essential for TXA2-induced prostate cancer (PCa) cell migration. Moreover, agonist-activation of TPα/TPβ induced phosphorylation of histone H3 at Thr11 (H3Thr11), a PRK1-catalysed marker of androgen-induced chromatin remodelling and transcriptional activation. This was the first demonstration that the TXA2/TP axis can lead to epigenetic changes previously only associated with androgens. As PRK1/PKN1 is a member of a wider subfamily that also includes PRK2/PKNγ and PRK3/PKNβ which, like PRK1, are widely implicated in cancers, we sought to investigate if PRK2 and PRK3 may interact with TPα/TPβ. Both PRK2 and PRK3 were found to interact with TPα and TPβ, interactions dynamically regulated following TP-agonist activation. Activation of the TPs also led to phosphorylation and catalytic activation of all three kinases. Furthermore, PRK1 and PRK2, but not PRK3, interacted with TPα and TPβ in PC-3 cells, while targeted disruption of PRK1 and PRK2, but not PRK3, impaired TP-mediated H3Thr11 phosphorylation, cell proliferation and migration of PC-3 cells. Considering the critical roles of TPα/TPβ and of the PRKs in cancer progression, the discovery of these distinct, yet regulated, interactions is functionally significant, not least in prostate cancer but also in other pathophysiologies where aberrant PRK1-3 &/or TPα/TPβ expression and function are implicated. Funded by the Irish Cancer Society, Health Research Board Ireland and the Movember Foundation (# PCI12KIN, MRCG/2012/3). Citation Format: Eamon P. Mulvaney, Aine G. O'Sullivan, B Therese Kinsella. Interaction of the protein kinase C-related kinases with the TPα and TPβ isoforms of the T prostanoid receptor: role in thromboxane-induced neoplastic responses. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 49. doi:10.1158/1538-7445.AM2015-49