Protein Kinase C Alpha is a Central Node for Tumorigenic Transcriptional Networks in Human Prostate Cancer

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 PKC & alpha; 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 PKC & alpha; expression. IHC analysis showed abnormal upregulation of PKC & alpha; in human primary prostate tumors. Interestingly, silencing PKC & alpha; 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 PKC & alpha; exerts a profound control of gene expression, particularly over genes and transcriptional networks associated with cell-cycle progression and E2F transcription factors. PKC & alpha; RNAi depletion from PC3 prostate cancer cells led to a reduction in the expression of proinflammatory cytokine and epithelial-to-mesenchymal transition (EMT) genes, as well as a prominent downregulation of the immune checkpoint ligand PD-L1. This PKC & alpha;-dependent gene expression profile was corroborated in silico us- ing human prostate cancer databases. Our studies established PKC & alpha; as a multifunctional kinase that plays pleiotropic roles in prostate cancer, par- ticularly by controlling genetic networks associated with tumor growth and progression. The identification of PKC & alpha; as a protumorigenic kinase in human prostate cancer provides strong rationale for the development of therapeutic approaches toward targeting PKC & alpha; or its effectors. Significance: PKC & alpha; was found to be aberrantly expressed in human prostate cancer. Silencing the expression of this kinase from aggressive prostate cancer cell lines reduces their proliferative, tumorigenic, and in- vasive properties. In addition, our findings implicate PKC & alpha; as a major node for transcriptional regulation of tumorigenic, inflammatory, and EMT networks in prostate cancer, highlighting its potential relevance as a therapeutic target.

Automated summary

Aberrant expression of protein kinase C (PKC) isozymes is a hallmark of cancer. The classical/conventional PKCα isozyme has been associated with tumor suppression in most cancer types, but in aggressive prostate cancer cells, high expression of PKCα is required for their mitogenic activity. Mechanistic analysis revealed that PKCα controls gene expression, particularly genes and transcriptional networks associated with cell-cycle progression and E2F transcription factors. Silencing PKCα expression in aggressive prostate cancer cells impairs cell-cycle progression, proliferation, invasion, and tumorigenic activity.