The pro-oncogenic kinase PKCε is overexpressed in human prostate cancer and cooperates with loss of the tumor suppressor Pten for the development of prostatic adenocarcinoma. However, the effectors driving PKCε-mediated phenotypes remain poorly defined. Here, using cellular and mouse models, we showed that PKCε overexpression acts synergistically with Pten loss to promote NF-κB activation and induce cyclooxygenase-2 (COX-2) expression, phenotypic traits which are also observed in human prostate tumors. Targeted disruption of PKCε from prostate cancer cells impaired COX-2 induction and PGE₂ production. Notably, COX-2 inhibitors selectively killed prostate epithelial cells overexpressing PKCε, and this ability was greatly enhanced by Pten loss. Long-term COX-2 inhibition markedly reduced adenocarcinoma formation, as well as angiogenesis in a mouse model of prostate-specific PKCε expression and Pten loss. Overall, our results provide strong evidence for the involvement of the canonical NF-κB pathway and its target gene COX2 as PKCε effectors, and highlight the potential of PKCε as a useful biomarker for the use of COX inhibition for chemopreventive and/or chemotherapeutic purposes in prostate cancer.

中文翻译：

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COX-2介导PKCε在前列腺癌中的促肿瘤作用。

促癌激酶PKCε在人前列腺癌中过表达，并与肿瘤抑制因子Pten的缺失协同作用，导致前列腺腺癌的发展。但是，驱动PKCε介导的表型的效应子仍然不清楚。在这里，使用细胞和小鼠模型，我们表明PKCε过表达与Pten缺失协同作用，以促进NF-κB激活并诱导环氧合酶2（COX-2）表达，这也是在人类前列腺肿瘤中观察到的表型特征。前列腺癌细胞对PKCε的靶向破坏损害了COX-2的诱导和PGE ₂生产。值得注意的是，COX-2抑制剂选择性杀死了过表达PKCε的前列腺上皮细胞，并且这种能力因Pten缺失而大大增强。在前列腺特异性PKCε表达和Pten缺失的小鼠模型中，长期抑制COX-2可以显着减少腺癌的形成以及血管生成。总体而言，我们的结果为规范的NF-κB途径及其靶基因COX2作为PKCε效应子的参与提供了有力证据，并突出了PKCε作为将COX抑制用于化学预防和/或化学治疗目的的有用生物标志物的潜力。前列腺癌。