Docosahexaenoic acid inhibits cancer cell growth via p27Kip1, CDK2, ERK1/ERK2, and retinoblastoma phosphorylation.
Docosahexaenoic acid (DHA), a PUFA of the n-3 family, inhibited the growth of FM3A mouse mammary cancer cells by arresting their progression from the late-G(1) to the S phase of the cell cycle. DHA upregulated p27(Kip1) levels by inhibiting phosphorylation of mitogen-activated protein (MAP) kinases, i.e., ERK1/ERK2. Indeed, inhibition of ERK1/ERK2 phosphorylation by DHA, U0126 [chemical MAPK extracellularly signal-regulated kinase kinase (MEK) inhibitor], and MEK(SA) (cells expressing dominant negative constructs of MEK) resulted in the accumulation of p27(Kip1). MAP kinase (MAPK) inhibition by DHA did not increase p27(Kip1) mRNA levels. Rather, this fatty acid stabilized p27(Kip1) contents and inhibited MAPK-dependent proteasomal degradation of this protein. DHA also diminished cyclin E phosphorylation, cyclin-dependent kinase-2 (CDK2) activity, and phosphorylation of retinoblastoma protein in these cells. Our study shows that DHA arrests cell growth by modulating the phosphorylation of cell cycle-related proteins.
Khan
Naim A
NA
Unité Propre de Recherche de l'Enseignement Supérieure-Lipides & Nutrition, Faculty of Life Sciences, University of Burgundy, Dijon, France. naim.khan@u-bourgogne.fr
Nishimura
Kazuhiro
K
Aires
Virginie
V
Yamashita
Tomoko
T
Oaxaca-Castillo
David
D
Kashiwagi
Keiko
K
Igarashi
Kazuei
K
D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019927:Cyclin E / Q000096:biosynthesis; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger; D012175:Retinoblastoma / Q000378:metabolism*; D015854:Up-Regulation
D019927:Cyclin E; D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004281:Docosahexaenoic Acids; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D020928:Mitogen-Activated Protein Kinases