Phenylacetate inhibits growth and modulates cell cycle gene expression in renal cancer cell lines.
BACKGROUND
Phenylacetate (PA), an aromatic fatty acid, is now undergoing evaluation as a potential anticancer reagent. Our previous study showed that PA induces cell growth inhibition in prostate cancer cells. Here, we investigated whether PA is effective against three renal cancer cell lines in vitro.


METHODS
The cell viability of PA-treated renal carcinoma cell lines (Caki-1, Os-RC-2 and RCC10) was assessed by trypan-blue exclusion and cell cycle distribution by flow cytometry. The cell cycle-regulatory protein expression was evaluated by Western blot, immunoprecipitation and kinase assay.


RESULTS
Growth inhibition occurred with PA treatment at a dose of 2-5 mM and an increased percentage of cells in G1 after 24 hours of exposure. Reduced phosphorylation of the retinoblastoma protein (Rb) and CDK2 activity, increased expression of p21Cip1 and enhanced binding of p21Cip1 to CDK2 were observed following treatment with PA.


CONCLUSIONS
Overall, these results suggest that p21Cip1 is a critical target in PA-mediated cell growth inhibition in RCC cells playing a key role in CDK2 inactivation, hypophosphorylation of pRb and subsequent G1 cell cycle arrest.
Franco
Omar E
OE
Department of Urology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
Onishi
Takehisa
T
Umeda
Yoshiki
Y
Soga
Norihito
N
Wakita
Toshiaki
T
Arima
Kiminobu
K
Yanagawa
Makoto
M
Sugimura
Yoshiki
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D042846:CDC2-CDC28 Kinases; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018816:Genes, cdc / Q000187:drug effects*; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010648:Phenylacetates / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006131:Growth Inhibitors; D009363:Neoplasm Proteins; D010648:Phenylacetates; D011518:Proto-Oncogene Proteins; 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; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; C025136:phenylacetic acid