Sodium ion channels as potential therapeutic targets for cancer metastasis

Voltage-Gated Sodium Channel NaV1.7 Inhibitors with Potent Anticancer Activities in Medullary Thyroid Cancer Cells

“…Based on a preliminary screening using RT-qPCR against two genes, SCN9A (NaV1.7) and SLC9A1 (NHE1), compound SV188 was selected for further evaluation, as it substantially lowered the expression of SLC9A1 (NHE1) and SCN9A (NaV1.7) compared to the corresponding controls (Figure 5C). Next, we tested SV188 against the NaV1.5, NaV1.6, and NaV1.7 channels that have been reported to be involved in cancer cells' migration and invasion [41,70]. The results showed that the treatment of SV188 at 5 µM for 48 h significantly decreased the mRNA expression of NaV1.7 and increased the mRNA expression of NaV1.5, with no significant effect on the mRNA expression of NaV1.6 (Figure 6).…”

“…A few examples of such channels are Na V 1.5 in breast [40,51,52], colon [49], and ovarian cancers [64]; Na V 1.6 in cervical cancer [65]; and Na V 1.7 in prostate [66,67], gastric [34], lung [68], and endometrial cancers [69]. Over the past decade, VGSCs subtypes Na V 1.5, Na V 1.6, and Na V 1.7 have been the most-reported isoforms that are shown to influence migration and invasion [32,41,70]. We initially examined the mRNA expression levels of VGSCs isoforms Na V 1.5, Na V 1.6, and Na V 1.7 in NETs using pancreatic (BON), lung (H727), and thyroid (MZ-CRC-1 and TT) cells and observed that the aggressive MTC cells originated from lymph node metastasis; MZ-CRC-1 showed strong expression of channels Na V 1.5, Na V 1.6, and Na V 1.7.…”

“…Although the treatment of SV188 affected NaV1.5 expression, when comparing the expression of all three channels, the expression of NaV1.7 was 400-fold higher than that of NaV1.5 and 25-fold higher than that of NaV1.6 (Figure 2A); the effect on NaV1.7 is more likely to outweigh the effect on NaV1.5. Next, we tested SV188 against the Na V 1.5, Na V 1.6, and Na V 1.7 channels that have been reported to be involved in cancer cells' migration and invasion [41,70]. The results showed that the treatment of SV188 at 5 µM for 48 h significantly decreased the mRNA expression of Na V 1.7 and increased the mRNA expression of Na V 1.5, with no significant effect on the mRNA expression of Na V 1.6 (Figure 6).…”

“…The mechanism of how inhibition of sodium channels inhibits cancer metastases have not been fully elucidated. However, a plausible mechanism pathway for this effect could involve VGSCs' colocalized proteins such as NCX and NHE-1, as shown in the schematic in Figure 1C [33,36,70]. One of the important factors contributing to the metastasis is the ability of highly aggressive cancer cells to cause proteolytic degradation of the extracellular matrix (ECM), break away from the tumor site, enter the bloodstream, and travel to distant sites to initiate metastasis.…”

Malignant currents: sodium leak channel NALCN propels prostate cancer aggressiveness

“…In addition to Ca 2+ signals, alterations in Na + hemostasis are also indicative of aggressive disease (reviewed in Horne et al , 2021 ). The Na + leak channel NALCN, first reported in hippocampal neurons (Lu et al , 2007 ), is a membrane multiprotein complex involved in cell excitability and trafficking whose genetic modifications are associated with neurological disorders (Rahrmann et al , 2022 ).…”