Inhibition of translation initiation mediates the anticancer effect of then-3 polyunsaturated fatty acid eicosapentaenoic acid

Eicosapentaenoic acid (EPA), an n-3 polyunsaturated fatty acid that is abun dant in the fish-based diets of populations that exhibit a remarkably low i ncidence of cancer, exerts anticancer activity in vitro and in animal model s of experimental cancer. Here we define the molecular basis for the antica ncer effects of EPA, EPA inhibits cell division by inhibiting translation i nitiation. 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 alpha, resulting in inhibition of protein synthesis at the level of translation initiation, preferentially re ducing the synthesis and expression of growth-regulatory proteins, includin g G1 cyclins, and causes cell cycle arrest in G(1), In a KLN-205 squamous c ell carcinoma mouse model, daily oral administration of EPA resulted in a s ignificant 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 G(0)-G (1), 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.