Journal
JOURNAL OF LIPID RESEARCH
Volume 47, Issue 10, Pages 2306-2313Publisher
ELSEVIER
DOI: 10.1194/jlr.M600269-JLR200
Keywords
fatty acids; cell cycle; cyclin-dependent kinase
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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 MEKSA (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.jlr Our study shows that DHA arrests cell growth by modulating the phosphorylation of cell cycle-related proteins. - Khan, N. A., K. Nishimura, V. Aires, T. Yamashita, D. Oaxaca-Castillo, K. Kashiwagi, and K. Igarashi. Docosahexaenoic acid inhibits cancer cell growth via p27(Kip1), CDK2, ERK1/ERK2, and retinoblastoma phosphorylation.
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