siRNA knockdown of ribosomal protein gene RPL19 abrogates the aggressive phenotype of human prostate cancer.

We provide novel functional data that posttranscriptional silencing of gene RPL19 using RNAi not only abrogates the malignant phenotype of PC-3M prostate cancer cells but is selective with respect to transcription and translation of other genes. Reducing RPL19 transcription modulates a subset of genes, evidenced by gene expression array analysis and Western blotting, but does not compromise cell proliferation or apoptosis in-vitro. However, growth of xenografted tumors containing the knocked-down RPL19 in-vivo is significantly reduced. Analysis of the modulated genes reveals induction of the non-malignant phenotype principally to involve perturbation of networks of transcription factors and cellular adhesion genes. The data provide evidence that extra-ribosomal regulatory functions of RPL19, beyond protein synthesis, are critical regulators of cellular phenotype. Targeting key members of affected networks identified by gene expression analysis raises the possibility of therapeutically stabilizing a benign phenotype generated by modulating the expression of an individual gene and thereafter constraining a malignant phenotype while leaving non-malignant tissues unaffected.

PRKC-ζ Expression Promotes the Aggressive Phenotype of Human Prostate Cancer Cells and Is a Novel Target for Therapeutic Intervention.

We show protein kinase C-zeta (PKC-ζ) to be a novel predictive biomarker for survival from prostate cancer (P < 0.001). We also confirm that transcription of the PRKC-ζ gene is crucial to the malignant phenotype of human prostate cancer. Following siRNA silencing of PRKC-ζ in PC3-M prostate cancer cells, stable transfectant cell line si-PRKC-ζ-PC3-M(T1-6) is phenotypically nonmalignant in vitro and in vivo. Genome-wide expression analysis identified 373 genes to be differentially expressed in the knockdown cells and 4 key gene networks to be significantly perturbed during phenotype modulation. Functional interconnection between some of the modulated genes is revealed, although these may be within different regulatory pathways, emphasizing the complexity of their mutual interdependence. Genes with altered expression following PRKC-ζ knockdown include HSPB1, RAD51, and ID1 that we have previously described to be critical in prostatic malignancy. Because expression of PRKC-ζ is functionally involved in promoting the malignant phenotype, we propose PKC-ζ as a novel and biologically relevant target for therapeutic intervention in prostate cancer.