Protein kinase cepsilon 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 Cepsilon (PKCepsilon), an oncogenic protein capable of promoting autocrine cell-signaling events. Gene transfer experiments demonstrated that PKCepsilon 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 G(1) cyclins, c-myc, and caveolin-1. Coimmunoprecipitation experiments indicated that PKCepsilon was associated with members of the extracellular signal-regulated kinase signaling cascade and the scaffolding protein caveolin-1. Caveolin-1, produced by LNCaP cells overexpressing PKCepsilon, 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 PKCepsilon 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 PKCepsilon expression may be sufficient to maintain prostate cancer growth and survival after androgen ablation.
Wu
Daqing
D
Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27858, USA.
Foreman
Tonia L
TL
Gregory
Christopher W
CW
McJilton
Meagan A
MA
Wescott
Ginger G
GG
Ford
O Harris
OH
Alvey
Rudolf F
RF
Mohler
James L
JL
Terrian
David M
DM
D051242:Caveolin 1; D022461:Caveolins / Q000096:biosynthesis; D002455:Cell Division / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D018450:Disease Progression; D016193:G1 Phase / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D009364:Neoplasm Recurrence, Local / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051744:Protein Kinase C-epsilon; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection
C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D018076:DNA, Complementary; D007527:Isoenzymes; D016376:Oligonucleotides, Antisense; D019908:Proto-Oncogene Proteins c-raf; C497255:PRKCE protein, human; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D020928:Mitogen-Activated Protein Kinases