285 - Silencing FXYD3 Protein in Human Breast Cancer Cells Enhances Oxidative Stress of Doxorubicin and Gamma Irradiation

Abstract

FXYD3, also known as mammary tumor protein 8, is overexpressed in several common cancers, including in many breast cancers. We examined if such overexpression might protect Na+/K+-ATPase and cancer cells against the high levels of oxidative stress characteristic of many tumors and often induced by cancer treatments. Expression of FXYD3 in MCF-7 breast cancer cells was ~8-fold and ~2-fold higher than in non-cancer MCF-10A cells and MDA-MB-468 cancer cells, respectively. A ~50% reduction in FXYD3 expression increased glutathionylation of the β1 Na+/K+-ATPase subunit and reduced Na+/K+-ATPase activity by ~50%, consistent with the role of FXYD3 to facilitate reversal of glutathionylation of the β1 subunit of Na+/K+-ATPase and glutathionylation-induced inhibition of Na+/K+-ATPase. Treatment of MCF-7 and MDA-MB- 468 cells with doxorubicin or γ-radiation decreased cell viability and induced apoptosis. The treatments up-regulated FXYD3 expression in MCF-7 but not in MDA-MB-468 cells and suppression of FXYD3 in MCF-7 but not in MDA-MB-468 cells amplified effects of treatments on Na+/K+-ATPase activity and treatment-induced cell death and apoptosis. Overexpression of FXYD3 may be a marker of resistance to cancer treatments and a potentially important therapeutic target.