Effect of naringenin at hypoxic conditions on voltage-gated sodium channel-mediated cancer cell motility

Hypoxia refers to fewer oxygen levels than normal conditions. In growing tumors, hypoxic conditions (oxygen deficiency) arise due to insufficient vascularization and the remote location of some tumor areas from the blood vessel. In response, tumor cells adapt to hypoxic conditions to sustain survival. Hypoxia-inducible factor (HIF) induces the expression of genes related to cell survival, angiogenesis, apoptosis, invasion, and metastases. There is some evidence that hypoxia supports voltage-gated sodium channel (VGSC) mediated cell movement and invasion. There are increasing findings that VGSCs are associated with metastatic cell behavior in many cancer cells such as prostate, breast, lung, etc. The metastatic behavior of PC-3 prostate cancer cells is related to VGSCs, and SCN8A encodes the VGSCs of these cells. This study aimed to investigate the effect of naringenin on the PC-3 prostate cancer cell movement in normoxia and hypoxia. For this purpose, cell proliferation analysis was performed by using Alamar blue. The effect of naringenin on the movement of the cell in a lateral direction was determined by performing wound healing assay. The intracellular sodium ion concentrations ([Na+ ]i) were measured by the inductive coupled plasma spectroscopy (ICP) method. Concentrations of naringenin that did not affect cell proliferation were determined as 75 and 100 µM. At these concentrations, naringenin did not affect cell motility in both conditions. According to the results of the ICP analysis, it was noted that the [Na+ ]i in the naringenin-treated group decreased compared to the control group (C: 59.5mM; NAR75: 47.8mM; NAR100: 54.8mM) in normoxia, but it increased in hypoxia (C: 47.7mM; NAR75: 51.6mM; NAR100: 61.9mM). When all the results are evaluated together, it has been revealed that naringenin can increase the movement of human prostate cancer PC3 cells in hypoxic conditions, while it does not affect the movement of it in normoxia. For this reason, we would like to emphasize that naringenin should be used cautiously, especially by cancer patients.