Voltage-gated sodium channel Nav1.5 promotes tumor progression and enhances chemosensitivity to 5-fluorouracil in colorectal cancer

• Published in: Cancer letters 2021-03, Vol.500, p.119-131
• Main Authors: Sui, Qiaoqi, Peng, Jianhong, Han, Kai, Lin, Junzhong, Zhang, Rongxin, Ou, Qingjian, Qin, Jiayi, Deng, Yuxiang, Zhou, Wenhao, Kong, Lingheng, Tang, Jinghua, Xiao, Binyi, Li, Yuan, Yu, Long, Fang, Yujing, Ding, Pei-Rong, Pan, Zhizhong
• Format: Article
• Language: English
• Subjects: 5-fluorouracil-stimulated apoptosis; Calcium influx; Calmodulin; Colorectal cancer; Nav1.5
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.12.017

Nav1.5, encoded by SCN5A, has been associated with metastasis in colorectal cancer (CRC). Here, we investigated the mechanism by which Nav1.5 regulates tumor progression and whether Nav1.5 influences chemosensitivity to 5-fluorouracil (5-FU) in CRCs. CRC cases were evaluated for Nav1.5 expression. Elevated Nav1.5 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, Nav1.5 stabilized the KRas-calmodulin complex to modulate Ras signaling, promoting Ca2+ influx through the Na+-Ca2+ exchanger and Ca2+ 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, Nav1.5 could progress to proliferation and metastasis through Ca2+/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. [Display omitted] •Nav1.5 promotes cell cycle and EMT process through Ras signaling in CRCs.•Nav1.5 increases Ca2+ influx and activates calmodulin/Ras signaling by enhancing the function of NCX and CRAC.•Activating calmodulin, Nav1.5 also enhances the sensitivity to 5-FU in CRCs.