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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >Regulation of protein kinase C-related kinase (PRK) signalling by the TP alpha and TP beta isoforms of the human thromboxane A(2) receptor: Implications for thromboxane- and androgen- dependent neoplastic and epigenetic responses in prostate cancer
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Regulation of protein kinase C-related kinase (PRK) signalling by the TP alpha and TP beta isoforms of the human thromboxane A(2) receptor: Implications for thromboxane- and androgen- dependent neoplastic and epigenetic responses in prostate cancer

机译：通过人血栓滤蛋A（2）受体的TPα和TPβ同种型对蛋白激酶C相关激酶（PRK）信号传导的调节：对前列腺癌中血栓素和雄激素依赖性肿瘤和外膜遗传反应的影响

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The prostanoid thromboxane (TX) A(2) and its T Prostanoid receptor (the TP) are increasingly implicated in prostate cancer (PCa). Mechanistically, we recently discovered that both TP alpha and TP beta form functional signalling complexes with members of the protein kinase C-related kinase (PRK) family, AGC- kinases essential for the epigenetic regulation of androgen receptor (AR)-dependent transcription and promising therapeutic targets for treatment of castrate-resistant prostate cancer (CRPC). Critically, similar to androgens, activation of the PRKs through the TXA(2)/TP signalling axis induces phosphorylation of histone H3 at Thrli (H3Thr11), a marker of androgen-induced chromatin remodelling and transcriptional activation, raising the possibility that TXA(2)-TP signalling can mimic and/or enhance AR-induced cellular changes even in the absence of circulating androgens such as in CRPC. Hence the aim of the current study was to investigate whether TXA(2)/TP-induced PRK activation can mimic and/or enhance AR-mediated cellular responses in the model androgen-responsive prostate adenocarcinoma LNCaP cell line. We reveal that TXA(2)/TP signalling can act as a neoplastic- and epigenetic-regulator, promoting and enhancing both AR-associated chromatin remodelling (H3Thrl 1 phosphorylation, WDR5 recruitment and acetylation of histone H4 at lysine 16) and AR-mediated transcriptional activation (e.g of the KLK3/prostate-specific antigen and TMPRSS2 genes) through mechanisms involving TP alpha/TP beta mediated-PRK1 and PRK2, but not PRK3, signalling complexes. Overall, these data demonstrate that TP alpha/TP beta can act as neoplastic and epigenetic regulators by mimicking and/or enhancing the actions of androgens within the prostate and provides further mechanistic insights into the role of the TXA(2)/TP signalling axis in PCa, including potentially in CRPC. (C) 2017 Elsevier B.V. All rights reserved.
机译：前列醇血栓素（Tx）A（2）及其T前列腺受体（TP）越来越涉及前列腺癌（PCA）。机械地，我们最近发现TPα和TPβ与蛋白激酶C相关激酶（PRK）家族的成员形成功能的信号络合物，对于雄激素受体（AR） - 依赖性转录和有前途的表观遗传调节至关重要治疗抗胆汁前列腺癌（CRPC）的治疗靶标。危重地，类似于雄激素，通过TXA（2）/ TP信号轴激活PRKS在THRLI（H3THR11）的组蛋白H3的磷酸化，雄激素诱导的染色质重塑和转录激活的标志物，提高了TXA的可能性（2即使在没有CRPC中的循环雌激素的情况下，也可以模拟和/或增强AR诱导的细胞变化。因此，目前研究的目的是研究TXA（2）/ TP诱导的PRK活化是否可以模拟和/或增强模型雌激素响应前列腺腺癌腺癌LNCAP细胞系中的AR介导的细胞反应。我们揭示了TXA（2）/ TP信号传导可以用作肿瘤和表观遗传调节剂，促进和增强AR相关的染色质重塑（H3Thll 1磷酸化，WDR5募集和组蛋白H4的丙酸盐16）和Ar介导的通过涉及TPα/TPβ介导的机制的转录激活（例如KLK3 /前列腺特异性抗原和TMPRSS2基因），但不是PRK3，信号配合物。总的来说，这些数据表明，TPα/TPβ可以通过模拟和/或增强前列腺内的雄激素的作用，并提供进一步的机械洞察TXA（2）/ TP信号轴的作用来充当肿瘤和表观遗传调节因子PCA，包括潜在的CRPC。 （c）2017 Elsevier B.v.保留所有权利。

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