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Experimental Therapeutics |
Laboratory for Membrane Transport, Harvard Medical School [S. S. P., R. F., H. A., A. K. C., S. H., E. K., J. A. H.], and Department of Medicine, Brigham and Women’s Hospital [A. S., J. A. H.], Boston, Massachusetts 02115
Eicosapentaenoic acid (EPA), an n-3 polyunsaturated fatty acid that is
abundant in the fish-based diets of populations that exhibit a
remarkably low incidence of cancer, exerts anticancer activity
in vitro and in animal models of experimental cancer.
Here we define the molecular basis for the anticancer effects of EPA.
EPA inhibits cell division by inhibiting translation initiation. This
is a consequence of the ability of EPA to release Ca2+ from
intracellular stores while inhibiting their refilling via capacitative
Ca2+ influx that results in partial emptying of
intracellular Ca2+ stores and thereby activation of protein
kinase R. Protein kinase R phosphorylates and inhibits eukaryotic
initiation factor 2
, resulting in inhibition of protein synthesis at
the level of translation initiation, preferentially reducing the
synthesis and expression of growth-regulatory proteins, including G1
cyclins, and causes cell cycle arrest in G1. In a KLN-205
squamous cell carcinoma mouse model, daily oral administration of EPA
resulted in a significant reduction of tumor size and expression of
cyclin D1 in the tumor tissues. Furthermore, EPA-treated tumors showed
a significant increase in the proportion of diploid cells, indicative
of cell cycle arrest in G0-G1, and a
significant reduction of malignant hypertetraploid cells. These results
characterize EPA as a member of an emerging new class of anticancer
compounds that inhibit translation initiation.
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