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Voltage-gated sodium channel Na v 1.5 promotes tumor progression and enhances chemosensitivity to 5-fluorouracil in colorectal cancer.
- Source :
-
Cancer letters [Cancer Lett] 2021 Mar 01; Vol. 500, pp. 119-131. Date of Electronic Publication: 2020 Dec 16. - Publication Year :
- 2021
-
Abstract
- Na <subscript>v</subscript> 1.5, encoded by SCN5A, has been associated with metastasis in colorectal cancer (CRC). Here, we investigated the mechanism by which Na <subscript>v</subscript> 1.5 regulates tumor progression and whether Na <subscript>v</subscript> 1.5 influences chemosensitivity to 5-fluorouracil (5-FU) in CRCs. CRC cases were evaluated for Na <subscript>v</subscript> 1.5 expression. Elevated Na <subscript>v</subscript> 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 <subscript>v</subscript> 1.5 stabilized the KRas-calmodulin complex to modulate Ras signaling, promoting Ca <superscript>2+</superscript> influx through the Na <superscript>+</superscript> -Ca <superscript>2+</superscript> exchanger and Ca <superscript>2+</superscript> 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 <subscript>v</subscript> 1.5 could progress to proliferation and metastasis through Ca <superscript>2+</superscript> /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.<br /> (Copyright © 2020 Elsevier B.V. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 500
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 33338532
- Full Text :
- https://doi.org/10.1016/j.canlet.2020.12.017