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

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.