Effects of low extracellular sodium on proliferation and invasive activity of cancer cells in vitro
Hyponatremia is the most common electrolyte disorder in hospitalized patients, and its etiopathogenesis is related to an underlying tumor in 14% of cases. Hyponatremia has been associated with a worse outcome in several pathologies, including cancer, in which the leading cause of this electrolyte alteration is the syndrome of inappropriate antidiuresis. The aim of this study was to analyze in vitro the effects of low extracellular [Na+] in cancer progression.
Materials and methods
We used a previously validated experimental model of chronic hyponatremia to characterize the effects of low extracellular [Na+] in different human cancer cell lines: pancreatic adenocarcinoma (PANC-1), neuroblastoma (SK-N-AS, SH-SY5Y), colorectal adenocarcinoma (HCT-8), chronic myeloid leukemia (K562).
Our results demonstrate a direct relationship between low [Na+], reduced cell adhesion and increased invasion and proliferation in all cell lines tested. Accordingly, the number of tumor colonies grown in soft agar and the expression of collagenases type IV (metalloproteinases 2 and 9) were markedly higher in cancer cells exposed to reduced extracellular [Na+]. Gene analysis showed an upregulation of molecular pathways involved in oxidative stress (heme oxygenase 1) and in proliferation and invasion (RhoA, ROCK-1, ROCK-2). The activation of RhoA/ROCK pathway was paralleled by a deregulation of the cytoskeleton-associated proteins, resulting in the promotion of actin cytoskeletal remodeling and cell invasion.
Overall, our data demonstrate for the first time that low [Na+] promotes cancer progression in vitro, thus suggesting that hyponatremia is not a simple bystander of disease severity in cancer.
KeywordsLow sodium [Na+] Tumor invasion Human cancer cells Gene expression Carcinogenesis
This research was supported by grants from Otsuka Pharmaceutical Europe Ltd., Accademia Nazionale di Medicina, PRIN 2017R5ZE2C.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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