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Disruption of the Temporal Activation of Ras-EGFR-MAPK Axis by Targeting a Critical Membrane Phospholipid Second Messenger
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The Ras-EGFR-MAPK signaling axis is chronically up-regulated in colon cancer, and pharmacological inhibition of signaling through Ras and/or EGFR has been shown to prevent colon tumor formation. Recent evidence suggests that production of the signaling lipid phosphatidic acid (PA) is essential for efficient Ras-EGFR-MAPK signaling. With respect to cancer prevention, there is a growing body of experimental, epidemiological and preclinical evidence indicating that fish oil-containing diets rich in n-3 polyunsaturated fatty acids (PUFA), e.g., DHA and its metabolic precursor EPA, are protective against colon tumorigenesis. We have demonstrated that DHA attenuates signaling of the Ras-EGFR-MAPK axis, however, the mechanism underlying this effect is not known. Therefore, we determined if the attenuation of Ras-EGFR signaling output by DHA is mediated via reduction of PA production. For this purpose, the young adult mouse colonocyte (YAMC) cell model expressing a FRET biosensor capable of monitoring cellular levels of K-Ras activation was utilized in conjunction with fluorescence microscopy techniques to monitor temporal changes of activated K-Ras levels following growth factor stimulation. Elucidating K-Ras as a molecular target of dietary bioactives is noteworthy because establishing a causal role of n-3 PUFA in colon cancer prevention would have a major translational impact due to their safety and tolerance.
Cortes Acosta, Sergio David (2016). Disruption of the Temporal Activation of Ras-EGFR-MAPK Axis by Targeting a Critical Membrane Phospholipid Second Messenger. Undergraduate Research Scholars Program. Available electronically from