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Inhibition
of translation initiation mediates the anticancer effect of the n-3
polyunsaturated fatty acid eicosapentaenoic acid
Palakurthi SS, Fluckiger R, Aktas H, Changolkar AK, Shahsafaei A, Harneit S,
Kilic E, Halperin JA
Laboratory for Membrane Transport, Harvard Medical School, Boston, Massachusetts
02115, USA
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.
PMID: 10850438 [PubMed - indexed for MEDLINE]
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