Centrosomal PKCbetaII and pericentrin are critical for human prostate cancer growth and angiogenesis.
Angiogenesis is critical in the progression of prostate cancer. However, the interplay between the proliferation kinetics of tumor endothelial cells (angiogenesis) and tumor cells has not been investigated. Also, protein kinase C (PKC) regulates various aspects of tumor cell growth, but its role in prostate cancer has not been investigated in detail. Here, we found that the proliferation rates of endothelial and tumor cells oscillate asynchronously during the growth of human prostate cancer xenografts. Furthermore, our analyses suggest that PKCbetaII was activated during increased angiogenesis and that PKCbetaII plays a key role in the proliferation of endothelial cells and tumor cells in human prostate cancer; treatment with a PKCbetaII-selective inhibitor, betaIIV5-3, reduced angiogenesis and tumor cell proliferation. We also find a unique effect of PKCbetaII inhibition on normalizing pericentrin (a protein regulating cytokinesis), especially in endothelial cells as well as in tumor cells. PKCbetaII inhibition reduced the level and mislocalization of pericentrin and normalized microtubule organization in the tumor endothelial cells. Although pericentrin has been known to be up-regulated in epithelial cells of prostate cancers, its level in tumor endothelium has not been studied in detail. We found that pericentrin is up-regulated in human tumor endothelium compared with endothelium adjacent to normal glands in tissues from prostate cancer patients. Our results suggest that a PKCbetaII inhibitor such as betaIIV5-3 may be used to reduce prostate cancer growth by targeting both angiogenesis and tumor cell growth.
Kim
Jeewon
J
Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, California 94305-5174, USA.
Choi
Yoon-La
YL
Vallentin
Alice
A
Hunrichs
Ben S
BS
Hellerstein
Marc K
MK
Peehl
Donna M
DM
Mochly-Rosen
Daria
D
D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000941:Antigens / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation; D018385:Centrosome / Q000201:enzymology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000008:administration & dosage / Q000138:chemical synthesis; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000941:Antigens; D008869:Microtubule-Associated Proteins; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; C086178:pericentrin; D011493:Protein Kinase C; D064546:Protein Kinase C beta