p27Kip1 is the key mediator of phenylacetate induced cell cycle arrest in human prostate cancer cells.
Treatment with millimolar concentrations of phenylacetate (PA), results in cytostasis, growth inhibition and differentiation in several human cancer cell lines, including prostate cancer. However, the molecular basis of PA-induced biological effects has not been elucidated in detail. In this study we focused on its influence on cell cycle events and investigated alterations in cell cycle regulators in androgen-dependent and independent human prostate cancer cell lines. FACS analysis revealed that suppression of cell growth by PA was due to G1 arrest, with reduced phosphorylation of the retinoblastoma protein (pRb) and CDK2 activity. Expression of p27Kip1 was increased, while p21Cip1, p53, cyclinD1 and cyclin E were not affected by PA. Binding of p27Kip1 to CDK2 increased significantly following treatment with PA. Furthermore, antisense p27Kip1 oligonucleotide attenuated the inhibitory effect of PA. Our results suggested that p27Kip1 might be a critical target in PA-mediated cell growth arrest in prostate cancer cells playing a key role in CDK2 inactivation followed by hypophosphorylation of pRB and subsequent G1 cell cycle arrest.
Onishi
T
T
Department of Urology, Mie University School ot Medicine, Japan. takehisa@clin.medic.mie-u.ac.jp
Yamakawa
K
K
Franco
O E
OE
Suzuki
R
R
Kawamura
J
J
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis; D016193:G1 Phase; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense; D010648:Phenylacetates / Q000494:pharmacology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D000964:Antimetabolites, Antineoplastic; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008869:Microtubule-Associated Proteins; D016376:Oligonucleotides, Antisense; D010648:Phenylacetates; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C025136:phenylacetic acid