1. Voltage-gated sodium channel Na v 1.5 promotes tumor progression and enhances chemosensitivity to 5-fluorouracil in colorectal cancer.
- Author
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Sui Q, Peng J, Han K, Lin J, Zhang R, Ou Q, Qin J, Deng Y, Zhou W, Kong L, Tang J, Xiao B, Li Y, Yu L, Fang Y, Ding PR, and Pan Z
- Subjects
- Apoptosis drug effects, Calmodulin ultrastructure, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Chemotherapy, Adjuvant adverse effects, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Disease Progression, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Epithelial-Mesenchymal Transition drug effects, Fluorouracil adverse effects, Gene Expression Regulation, Neoplastic drug effects, Humans, Multiprotein Complexes genetics, Multiprotein Complexes ultrastructure, Neoplasm Invasiveness genetics, Neoplasm Invasiveness pathology, Proto-Oncogene Proteins p21(ras) ultrastructure, Calmodulin genetics, Colorectal Neoplasms drug therapy, Fluorouracil pharmacology, NAV1.5 Voltage-Gated Sodium Channel genetics, Proto-Oncogene Proteins p21(ras) genetics
- Abstract
Na
v 1.5, encoded by SCN5A, has been associated with metastasis in colorectal cancer (CRC). Here, we investigated the mechanism by which Nav 1.5 regulates tumor progression and whether Nav 1.5 influences chemosensitivity to 5-fluorouracil (5-FU) in CRCs. CRC cases were evaluated for Nav 1.5 expression. Elevated Nav 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, Nav 1.5 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, Nav 1.5 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., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2021
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