Regulation of caveolin-1 expression and secretion by a protein kinase cepsilon signaling pathway in human prostate cancer cells.
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.
Wu
Daqing
D
Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA. wud@mail.ecu.edu
Terrian
David M
DM
D001483:Base Sequence; D015153:Blotting, Western; D051242:Caveolin 1; D022461:Caveolins / Q000096:biosynthesis / Q000235:genetics*; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000008:administration & dosage / Q000378:metabolism* / Q000502:physiology; D020935:MAP Kinase Signaling System; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000008:administration & dosage / Q000378:metabolism* / Q000502:physiology; D051744:Protein Kinase C-epsilon; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D017931:DNA Primers; D007527:Isoenzymes; D011944:Receptors, Androgen; C497255:PRKCE protein, human; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon