Protein Kinase C Has the Potential to Advance the Recurrence of Human Prostate Cancer

Prostatic epithelial cells that are capable of surviving in the absence of androgenic steroids were found to express protein kinase C (PKC ), an oncogenic protein capable of promoting autocrine cell-signaling events. Gene transfer experiments demonstrated that PKC overexpression was sufficient to transform androgen-dependent LNCaP cells into an androgen-independent variant that rapidly initiated tumor growth in vivo in both intact and castrated male nude mice. This transformation was associated with an accelerated rate of androgen-independent LNCaP cell proliferation, resistance to apoptosis, hyperphosphorylation of the mitogen-activated protein kinase extracellular signal-regulated kinase and transcriptional repressor protein retinoblastoma, and increased expression of E2F-1 and other 5 -cap-dependent mRNAs, including the G1 cyclins, c-myc, and caveolin-1. Coimmunoprecipitation experiments indicated that PKC was associated with members of the extracellular signalregulated kinase signaling cascade and the scaffolding protein caveolin-1. Caveolin-1, produced by LNCaP cells overexpressing PKC , was released into the medium, possibly through a Golgi-independent route, and significant growth inhibition was observed when these cells were cultured in the presence of an anti-caveolin-1 antiserum. Finally, antisense experiments established that endogenous PKC plays an important role in regulating the growth and survival of androgen-independent prostate cancer cells. This study provides several independent lines of evidence supporting the hypothesis that PKC expression may be sufficient to maintain prostate cancer growth and survival after androgen ablation.