Inhibition of translation initiation mediates the anticancer effect of the n-3 polyunsaturated fatty acid eicosapentaenoic acid.
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 2alpha, 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 initiaton.
Palakurthi
S S
SS
Laboratory for Membrane Transport, Harvard Medical School, Boston, Massachusetts 02115, USA.
Flückiger
R
R
Aktas
H
H
Changolkar
A K
AK
Shahsafaei
A
A
Harneit
S
S
Kilic
E
E
Halperin
J A
JA
D016475:3T3 Cells; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015118:Eicosapentaenoic Acid / Q000235:genetics / Q000494:pharmacology*; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D051379:Mice; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental; D010766:Phosphorylation; D011003:Ploidies; D014176:Protein Biosynthesis / Q000187:drug effects*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D014452:Ubiquitins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D019927:Cyclin E; D014452:Ubiquitins; D019938:Cyclin D1; D015118:Eicosapentaenoic Acid; D018631:ras Proteins; D002118:Calcium