Abstract
The prostanoid thromboxane (TX) A2 is increasingly implicated in neoplastic progression, including prostate cancer (PCa). Mechanistically, we recently identified protein kinase C-related kinase (PRK) 1 as a functional interactant of both the TPα and TPβ isoforms of the human T prostanoid receptor (TP). The interaction with PRK1 was not only essential for TPα/TPβ-induced PCa cell migration but also enabled the TXA2-TP axis to induce phosphorylation of histone H3 at Thr11 (H3Thr11), an epigenetic marker both essential for and previously exclusively associated with androgen-induced chromatin remodelling and transcriptional activation. PRK1 is a member of a subfamily of three structurally related kinases comprising PRK1/PKNα, PRK2/PKNγ and PRK3/PKNβ that are widely yet differentially implicated in various cancers. Hence, focusing on the setting of prostate cancer, this study investigated whether TPα and/or TPβ might also complex with PRK2 and PRK3 to regulate their activity and neoplastic responses. While TPα and TPβ were found in immune complexes with PRK1, PRK2 and PRK3 to regulate their activation and signalling, they do so differentially and in a TP agonist-regulated manner dependent on the T-loop activation status of the PRKs but independent of their kinase activity. Furthermore, TXA2-mediated neoplastic responses in prostate adenocarcinoma PC-3 cells, including histone H3Thr11 phosphorylation, was found to occur through a PRK1- and PRK2-, but not PRK3-, dependent mechanism. Collectively, these data suggest that TXA2 acts as both a neoplastic and epigenetic regulator and provides a mechanistic explanation, at least in part, for the prophylactic benefits of Aspirin in reducing the risk of certain cancers.
Highlights
The prostanoid thromboxane (TX) A2, synthesized from arachidonic acid by the sequential actions of cyclooxygenase (COX)-1/COX-2 and thromboxane A2 (TXA2) synthase predominantly in platelets and macrophages, plays a central role within the vasculature dynamically regulating platelet activation status and vascular tone [1, 2]
Focusing on the setting of prostate cancer, the aim of this study was to investigate whether TPα and/or TPβ might associate with and regulate the activity, including neoplastic responses, through PRK2/PKNγ and PRK3/PKNβ, AGC kinases that like PRK1/PKNα act downstream of RhoA and phosphatidylinositol 3’kinase (PI3’K)/PDK1 oncogenic signalling
The ability of PRK1, PRK2 or PRK3 to form complexes with TPα and TPβ in the metastatic prostate adenocarcinoma PC-3 cell line was investigated through co-immunoprecipitations using anti-TPα and anti-TPβ isoform-specific antibodies [26, 29]
Summary
The prostanoid thromboxane (TX) A2, synthesized from arachidonic acid by the sequential actions of cyclooxygenase (COX)-1/COX-2 and TXA2 synthase predominantly in platelets and macrophages, plays a central role within the vasculature dynamically regulating platelet activation status and vascular tone [1, 2]. Inhibiting TXA2 synthesis, action or both through use of Aspirin or TP antagonists is a key therapeutic strategy in the management of many diseases involving TXA2, including atherothrombosis and acute coronary syndrome. Numerous studies have demonstrated increased expression of COX-1 and COX-2 and of their prostanoid metabolites in a range of cancers [3]. Several longitudinal studies show that long-term daily use of Aspirin reduces the risk of many prevalent cancers including of the colon, oesophagus, lung and prostate [4,5,6]. While such studies do not specify which www.impactjournals.com/oncotarget
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