Voltage-gated sodium channel Na v 1.5 promotes tumor progression and enhances chemosensitivity to 5-fluorouracil in colorectal cancer.

Na _v 1.5, encoded by SCN5A, has been associated with metastasis in colorectal cancer (CRC). Here, we investigated the mechanism by which Na _v 1.5 regulates tumor progression and whether Na _v 1.5 influences chemosensitivity to 5-fluorouracil (5-FU) in CRCs. CRC cases were evaluated for Na _v 1.5 expression. Elevated Na _v 1.5 expression was associated with poor prognosis in CRCs, whereas stage II/III patients with upregulated SCN5A expression could have better survival after receiving 5-FU-based adjuvant chemotherapy. In CRC cells, SCN5A knockdown reduced the proliferation, migration and invasion. According to RNA sequencing, SCN5A knockdown inhibited both the cell cycle and epithelial-mesenchymal transition. In addition, Na _v 1.5 stabilized the KRas-calmodulin complex to modulate Ras signaling, promoting Ca ²⁺ influx through the Na ⁺ -Ca ²⁺ exchanger and Ca ²⁺ release-activated calcium channel. Meanwhile, SCN5A knockdown increased the 50% inhibitory concentration to 5-FU by upregulating 5-FU-stimulated apoptosis in CRCs. In conclusion, Na _v 1.5 could progress to proliferation and metastasis through Ca ²⁺ /calmodulin-dependent Ras signaling in CRC, and it could also enhance 5-FU-stimulated apoptosis. Clinically, patients with stage II/III CRCs with elevated SCN5A expression demonstrated poor prognosis, yet those patients could benefit more from 5-FU-based chemotherapy than patients with lower SCN5A expression.
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