title: Inhibition of colon cancer cell proliferation by the dietary compound conjugated linoleic acid is mediated by the CDK inhibitor p21CIP1/WAF1.
abstract: Our previous studies indicated that dietary conjugated linoleic acid (CLA) inhibits colon tumor cell proliferation in vitro and in vivo. To identify mechanisms by which CLA regulates growth arrest, the HT-29 human colon carcinoma cell line was treated with various physiological concentrations of CLA and analyzed by flow cytometry. We detected a dose-dependent increase in the percentage of cells arrested in G1 after CLA treatment that was accompanied by induction of the cyclin dependent kinase (CDK) inhibitor p21CIP1/WAF. CLA addition also led to increased p21 expression in HCT116 and SW480 cells, indicating that p21 induction is a general consequence of CLA treatment in colon cancer cells. Since both HT-29 and SW480 cells have mutant p53, our data indicate that p53 is not essential for induction of p21. In addition to an increase in p21 levels, HT-29 cell growth arrest was also accompanied by moderate decreases in Cyclin A, D1, E, and proliferating cell nuclear antigen (PCNA) levels. Following CLA treatment, p21 associated with and inhibited CDK4 and CDK2, and this correlated with reduced phosphorylation of retinoblastoma proteins. Increased association of p21 with PCNA was also detected. Dietary CLA inhibits cell cycle progression by inducing p21, which negatively regulates the growth promoting activities of CDK/cyclins and PCNA. These studies indicate that physiological concentrations of CLA inhibit growth of colon cancer cells with either wild-type or mutant p53, and may have therapeutic benefits in vivo.
authors.affiliation: Division of Life Sciences, Hallym University, Chunchon, Korea.
authors.forename: Do Y
authors.initials: DY
authors.lastname: Lim
authors.forename: Angela L
authors.initials: AL
authors.lastname: Tyner
authors.forename: Jae-Bong
authors.initials: JB
authors.lastname: Park
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Yung H
authors.initials: YH
authors.lastname: Choi
authors.forename: Jung H Y
authors.initials: JH
authors.lastname: Park
mesh_terms: D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004032:Diet; D006801:Humans; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D044243:Linoleic Acids, Conjugated; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; 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