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

Abstract

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.

c-Myc phosphorylation by PKCζ represses prostate tumorigenesis

“…This suggests that, although PKCζ mRNA levels could be highly up-regulated upon PCa disease progression, as previously reported (9), its protein levels are down-regulated. This is inconsistent with previous data that propose PKCζ as a predictive biomarker for survival in PCa (10). However, the antibody used for that study recognizes both isoforms, PKCζ and PKCλ/ι, which precludes any conclusion on the specific role of PKCζ in those tumors.…”

Inhibition of Protein Kinase C/Twist1 Signaling Augments Anticancer Effects of Androgen Deprivation and Enzalutamide in Prostate Cancer

“…As well, in human prostate cancer tissues, PKC signaling was highly activated in CRPC specimens compared with hormone-na€ ve cancers (10). Similarly, PKC expression correlated with poor clinical parameters such as biochemical failure after radical prostatectomy, Gleason score, and clinical stage (22,23). These observations collectively implicate PKCs in the pathogenesis of prostate cancer, and suggest that the PKC signaling pathway, similar to Twist1, may be a promising therapeutic target in prostate cancer.…”

“…Conversely, deletion of PKC-e in TRAMP mice inhibited prostate cancer development and metastasis (18). Similarly, PKC-b is also shown to be augmented in prostate cancer and implicated in prostate cancer development (19)(20)(21), as supported by numerous in vitro studies showing that inhibition of PKC signaling attenuated prostate cancer proliferation (21)(22)(23). Although, PKCs have also been implicated in castration resistance, and constitutively active PKC signaling promoted androgen-dependent, as well as castration-resistant proliferation of prostate cancer cells (24).…”

Protein Kinase C (PKC) Isozymes and Cancer

“…Spisulosine (ES-285), which is a marine compound that has an anticancer activity, induces the death of prostate cancer cells through ceramide accumulation and PKC activation [453]. In a recent study, PKC was also shown to be involved in promoting the aggressive phenotype of LNCaP cells [454], while another study postulated that its overexpression inhibits invasive and metastatic activity in Dunning R-3327 rat prostate cancer cells [455]. Further, PKC activation is required for androgen-dependent cell proliferation in prostate cancer LNCaP cells and during the transition of androgen-dependent to androgen-independent prostate cancer cells [456].…”