Docosahexaenoic acid inhibits cancer cell growth via p27Kip1, CDK2, ERK1/ERK2, and retinoblastoma phosphorylation

Abstract

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 p27Kip1 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 p27Kip1. MAP kinase (MAPK) inhibition by DHA did not increase p27Kip1 mRNA levels. Rather, this fatty acid stabilized p27Kip1 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. Copyright ©2006 by the American Society for Biochemistry and Molecular Biology, Inc.