Suppression of PPARβ, and DHA treatment, inhibit NaV1.5 and NHE-1 pro-invasive activities.

Peroxisome proliferator-activated receptor β (PPARβ) and NaV1.5 voltage-gated sodium channels have independently been shown to regulate human breast cancer cell invasiveness. The n-3 polyunsaturated docosahexaenoic acid (DHA, 22:6n-3), a natural ligand of PPAR, is effective in increasing survival and chemotherapy efficacy in breast cancer patient with metastasis. DHA reduces breast cancer cell invasiveness and it also inhibits PPARβ expression. We have shown previously that NaV1.5 promotes MDA-MB-231 breast cancer cells invasiveness by potentiating the activity of Na(+)/H(+) exchanger type 1 (NHE-1), the major regulator of H(+) efflux in these cells. We report here that DHA inhibited NaV1.5 current and NHE-1 activity in human breast cancer cells, and in turn reduced NaV1.5-dependent cancer cell invasiveness. For the first time, we show that antagonizing PPARβ, or inhibiting its expression, reduced NaV1.5 mRNA and protein expression and NaV1.5 current, as well as NHE-1 activity and cell invasiveness. Consistent with these results, the DHA-induced reduction of both NaV1.5 expression and NHE-1 activity was abolished in cancer cells knocked-down for the expression of PPARβ (shPPARβ). This demonstrates a direct link between the inhibition of PPARβ expression and the inhibition of Nav1.5/NHE-1 activities and breast cancer cell invasiveness. This study provides new mechanistic data advocating for the use of natural fatty acids such as DHA to block the development of breast cancer metastases.