Regulation of caveolin-1 expression and secretion by a protein kinase cepsilon signaling pathway in human prostate cancer cells

Abstract

Caveolin-1, androgen receptor, c-Myc, and protein kinase Cepsilon (PKCepsilon) proteins are overrepresented in most advanced prostate cancer tumors. Previously, we demonstrated that PKCepsilon has the capacity to enhance the expression of both caveolin-1 and c-Myc in cultured prostate cancer cells and is sufficient to induce the growth of androgen-independent tumors. In this study, we have uncovered further evidence of a functional interplay among these proteins in the CWR22 model of human prostate cancer. The results demonstrated that PKCepsilon expression was naturally up-regulated in recurrent CWR22 tumors and that this oncoprotein was required to sustain the androgen-independent proliferation of CWR-R1 cells in culture. Gene transfer experiments demonstrated that PKCepsilon had the potential to augment the expression and secretion of a biologically active caveolin-1 protein that supports the growth of the CWR-R1 cell line. Antisense and pharmacological experiments provided additional evidence that the sequential activation of PKCepsilon, mitogen-activated protein kinases, c-Myc, and androgen receptor signaling drove the downstream expression of caveolin-1 in CWR-R1 cells. Finally, we demonstrate that mitogen-activated protein kinases were required downstream of PKCepsilon to derepress the transcriptional elongation of the c-myc gene. Our findings support the hypothesis that PKCepsilon may advance the recurrence of human prostate cancer by promoting the expression of several important downstream effectors of disease progression.