Protein kinase C-related kinase 1 and 2 play an essential role in thromboxane-mediated neoplastic responses in prostate cancer

Abstract

The prostanoid thromboxane (TX) A 2 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 TP` and TPβ isoforms of the human T prostanoid receptor (TP). The interaction with PRK1 was not only essential for TP`/TPβ-induced PCa cell migration but also enabled the TXA 2 -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/PKN`, 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 TP` and/or TPβ might also complex with PRK2 and PRK3 to regulate their activity and neoplastic responses. While TP` 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, TXA 2 -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 TXA 2 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.

Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

“…Added to this complexity, we recently established that the TPα and TPβ isoforms differentially associate with and regulate signalling by the other individual members of the PRKs (PRK1/PKNα, PRK2/PKNγ, PRK3/PKNβ) (57). Furthermore, consistent with our previous studies involving PRK1 (48), siRNA disruption of PRK1 and PRK2, but not PRK3, expression eliminates TP-mediated cancer cell responses (proliferation, anchorage-independent growth, migration) and H3pThr11 phosphorylation in the prostate carcinoma PC-3 cell line (57). Identification of a direct, functional interaction of both TPα and TPβ with the PRKs provides yet another molecular link accounting for the role of TXA 2 in tumour progression, particularly in prostate and other cancers in which the TXA 2 -TP and PRKs are increasingly implicated.…”

PKN2 is essential for mouse embryonic development and proliferation of mouse fibroblasts

“…) and prostate adenocarcinoma PC‐3 cells (O'Sullivan et al . ), hyaluronan‐induced migration of astrocytes (Bourguignon et al . ) and control of cell cycle (G2/M transition and exit from cytokinesis) in Hela S3 cells (Schmidt et al .…”

“…PKN isoforms have been regarded as effectors of Rho family GTPases, and PKN2 (also known as PRK2/PKNc) is reported to bind to RhoA, RhoB, RhoC and Rac (Quilliam et al 1996;Vincent & Settleman 1997;Hutchinson et al 2013) in mammalian tissues. So far, there have been accumulating reports about the functions of PKN2, derived using mammalian cell culture experiments: PKN2 has been suggested to play critical roles in actin stress fiber formation in NIH 3T3 cells (Vincent & Settleman 1997), keratinocyte cell-cell adhesion under the control of Rho family GTPase (Calautti et al 2002;Bourguignon et al 2004), promotion of apical junction maturation of bronchial cells (Wallace et al 2011), neoplastic responses such as migration in 5637 bladder tumor cells (Lachmann et al 2011) and prostate adenocarcinoma PC-3 cells (O'Sullivan et al 2015), hyaluronan-induced migration of astrocytes (Bourguignon et al 2007) and control of cell cycle (G2/M transition and exit from cytokinesis) in Hela S3 cells (Schmidt et al 2007). To understand the in vivo physiological function of PKN2 using an Genes to Cells organismal model, we targeted the PKN2 gene and generated PKN2 À/À mice.…”

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

“…Hence, imbalances in the levels of TXA 2 , or of TXA 2 S or of the TP have been implicated in a range of cardiovascular, renal and pulmonary diseases, including in PAH [2][3][4][5]. The TXA 2 -TP axis also regulates key mitogenic/ERK and RhoA-mediated signalling cascades, explaining, at least in part, the role of TXA 2 in increasing cell proliferation and migration such as occurs in restenosis, vascular remodelling, and in a range of cancers in which the TXA 2 -TP axis is increasingly implicated [2][3][4][5][6][7][8].…”