Protein kinase Cdelta signaling downstream of the EGF receptor mediates migration and invasiveness of prostate cancer cells.
Tumor progression to the invasive phenotype occurs secondary to upregulated signaling from growth factor receptors that drive key cellular responses like proliferation, migration, and invasion. We hypothesized that Protein kinase Cdelta (PKCdelta)-mediated transcellular contractility is required for migration and invasion of prostate tumor cells. Two invasive human prostate cancer cell lines, DU145 cells overexpressing wildtype human EGFR (DU145WT) and PC3 cells, were studied. PKCdelta is overexpressed in these cells relative to normal prostate epithelial cells, and is activated downstream of EGFR leading to cell motility via modulation of myosin light chain activity. Abrogation of PKCdelta using Rottlerin and specific siRNA significantly decreased migration and invasion of both cell lines in vitro. Both PKCdelta and phosphorylated PKCdelta protein levels were higher in human prostate cancer tissue relative to normal donor prostate as assessed by Western blotting and immunohistochemistry. Thus, we conclude that PKCdelta inhibition can limit migration and invasion of prostate cancer cells.
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh VAMC, Pittsburgh, PA 15261, USA.
Sourabh
S
Kharait
Rajiv
R
Dhir
Douglas
D
Lauffenburger
Alan
A
Wells
D002277:Carcinoma / Q000201:enzymology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008297:Male; D018994:Myosin Light Chains / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D051745:Protein Kinase C-delta / Q000378:metabolism*; D015398:Signal Transduction
D018994:Myosin Light Chains; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D051745:Protein Kinase C-delta