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Journal of Lipid Research, Vol. 47, 2306-2313, October 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Docosahexaenoic acid inhibits cancer cell growth via p27^Kip1, CDK2, ERK1/ERK2, and retinoblastoma phosphorylation

Naim A. Khan^1,*, Kazuhiro Nishimura, Virginie Aires^*, Tomoko Yamashita, David Oaxaca-Castillo, Keiko Kashiwagi and Kazuei Igarashi

^* Unité Propre de Recherche de l'Enseignement Supérieure–Lipides & Nutrition, Faculty of Life Sciences, University of Burgundy, Dijon, France
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
Laboratoire de Biologie Cellulaire et Moléculaire, Faculty of Life Sciences, University of Burgundy, Dijon, France

Published, JLR Papers in Press, July 17, 2006.

¹ To whom correspondence should be addressed. e-mail: naim.khan{at}u-bourgogne.fr

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-G₁ 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.

Supplementary key words fatty acids • cell cycle • cyclin-dependent kinase

Abbreviations: AA, arachidonic acid; CDK, cyclin-dependent kinase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; ES medium, essential seiyaku medium; FCS, fetal calf serum; MAP, mitogen-activated protein; MAPK, MAP kinase; MEK, MAPK extracellularly signal-regulated kinase kinase; PMA, phorbol-12-myristate-13-acetate; pRb, retinoblastoma protein

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