Up-regulation of p21(WAF1/CIP1) levels leads to growth suppression of prostate cancer cell lines.
In a previous study, we found that TPA-mediated up-regulation of p21(WAF1/CIP1) induces growth arrest and differentiation of the human prostate cancer cell line TSU-Pr1. We investigated the effect of 12-O-tetra-decanoylphorbol-13-acetate (TPA) on growth and p21(WAF1/CIP1) protein levels in four prostate cancer cell lines. TPA treatment suppressed proliferation of the androgen-insensitive prostate cancer cell lines DU145 and PC-3. DU145 and PC-3 cells, however, showed neither morphological changes nor differentiation after TPA treatment. In contrast, TPA induced apoptosis of the androgen-sensitive prostate cancer cell line LNCaP. TPA induced up-regulation of p21(WAF1/CIP1) protein levels in all four cancer cell lines and this up-regulation was regulated by PKC in all four, but MAP kinase was associated with regulation only in TSU-Pr1 cells. Moreover, transient transfection with Adv-p21 resulted in growth arrest of all four cell lines. These data suggest that increased p21(WAF1/CIP1) production directly suppresses proliferation of prostate cancer cells regardless of androgen sensitivity. The pathway of TPA-induced increases in p21(WAF1/CIP1) levels was regulated by PKC. We thus conclude that p21(WAF1/CIP1) is a good candidate for use in treatment of prostate cancers because it suppresses proliferation of several prostate cancer cell lines.
Sugibayashi
Ryo
R
Department of Hygiene-Chemistry, Faculty of Pharmaceutical Sciences, Science University of Tokyo, Japan.
Kiguchi
Yoko
Y
Shimizu
Takahisa
T
Suzuki
Toshihiro
T
Hamada
Hirofumi
H
Takeda
Ken
K
D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate