Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Medicine, Einstein Medical Center Philadelphia, Philadelphia, PA 19141, USA.
Cancer Res Commun. 2022 Nov;2(11):1372-1387. doi: 10.1158/2767-9764.crc-22-0170. Epub 2022 Nov 8.
Aberrant expression of protein kinase C (PKC) isozymes is a hallmark of cancer. The different members of the PKC family control cellular events associated with cancer development and progression. Whereas the classical/conventional PKCα isozyme has been linked to tumor suppression in most cancer types, here we demonstrate that this kinase is required for the mitogenic activity of aggressive human prostate cancer cells displaying aberrantly high PKCα expression. Immunohistochemical analysis showed abnormal up-regulation of PKCα in human primary prostate tumors. Interestingly, silencing PKCα expression from aggressive prostate cancer cells impairs cell cycle progression, proliferation and invasion, as well as their tumorigenic activity in a mouse xenograft model. Mechanistic analysis revealed that PKCα exerts a profound control of gene expression, particularly over genes and transcriptional networks associated with cell cycle progression and E2F transcription factors. PKCα RNAi depletion from PC3 prostate cancer cells led to a reduction in the expression of pro-inflammatory cytokine and epithelial-to-mesenchymal transition (EMT) genes, as well as a prominent down-regulation of the immune checkpoint ligand PD-L1. This PKCα-dependent gene expression profile was corroborated using human prostate cancer databases. Our studies established PKCα as a multifunctional kinase that plays pleiotropic roles in prostate cancer, particularly by controlling genetic networks associated with tumor growth and progression. The identification of PKCα as a pro-tumorigenic kinase in human prostate cancer provides strong rationale for the development of therapeutic approaches towards targeting PKCα or its effectors.
蛋白激酶 C（PKC）同工酶的异常表达是癌症的一个标志。PKC 家族的不同成员控制着与癌症发生和发展相关的细胞事件。虽然经典/传统的 PKCα 同工酶与大多数癌症类型的肿瘤抑制有关，但在这里我们证明，这种激酶对于表现出异常高 PKCα 表达的侵袭性人类前列腺癌细胞的有丝分裂活性是必需的。免疫组织化学分析显示，人类原发性前列腺肿瘤中 PKCα 异常上调。有趣的是，沉默侵袭性前列腺癌细胞中的 PKCα 表达会损害细胞周期进程、增殖和侵袭，以及它们在小鼠异种移植模型中的致瘤活性。机制分析表明，PKCα 对基因表达具有深远的控制作用，特别是对与细胞周期进程和 E2F 转录因子相关的基因和转录网络。PC3 前列腺癌细胞中 PKCα RNAi 的耗竭导致促炎细胞因子和上皮-间充质转化（EMT）基因的表达减少，以及免疫检查点配体 PD-L1 的显著下调。使用人类前列腺癌数据库证实了这种 PKCα 依赖性基因表达谱。我们的研究确立了 PKCα 作为一种多功能激酶，在前列腺癌中发挥多种作用，特别是通过控制与肿瘤生长和进展相关的遗传网络。PKCα 作为人类前列腺癌中的促瘤激酶的鉴定为针对 PKCα 或其效应物开发治疗方法提供了强有力的理由。
