Effects of reduced extracellular sodium on proliferation and invasive activity of renal cell carcinoma cell lines.

Abstract

Hyponatremia is the most common electrolyte disorder in cancer patients and is associated with a worse outcome. This finding has also been reported in patients with metastatic renal cell carcinoma (mRCC). We have previously demonstrated that low extracellular sodium concentrations ([Na⁺]) increase cell proliferation and invasion in several human cancer cell lines. The aim of the present study was to evaluate in vitro the effects of mild [Na⁺] alterations on two mRCC cell lines, ACHN and Caki-1. After growth in reduced extracellular [Na⁺], we observed that even mild reductions of [Na⁺] significantly enhanced different key cancer cell features, including proliferation, invasion and migration. Furthermore, we observed a reduction in reactive oxygen species (ROS) levels in low [Na⁺], with a significant increase of the antioxidant Nrf2/HMOX-1 pathway. Since an excess of ROS causes cell death, this finding clarifies the role of Nrf2/HMOX-1 in maintaining the balance between oxidant and antioxidant species in the tumor environment, promoting cell survival. Although further clinical studies are needed, aiming for instance to determine whether serum [Na⁺] correction improves the outcome of patients with mRCC, our findings suggest that attention should be deserved to serum [Na⁺] in this setting.