Cargando…
CACNA2D3 Enhances the Chemosensitivity of Esophageal Squamous Cell Carcinoma to Cisplatin via Inducing Ca(2+)-Mediated Apoptosis and Suppressing PI3K/Akt Pathways
Resistance to platinum-based combination chemotherapy is the main cause of poor prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC). Previously, we showed that CACNA2D3 (voltage-dependent subunit alpha 2 delta 3 of a calcium channel complex) was significantly downregulated...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454090/ https://www.ncbi.nlm.nih.gov/pubmed/31001468 http://dx.doi.org/10.3389/fonc.2019.00185 |
_version_ | 1783409503031525376 |
---|---|
author | Nie, Changjun Qin, Xiaohui Li, Xiaoyan Tian, Baoqing Zhao, Ying Jin, Yuan Li, Yadan Wang, Qiang Zeng, Dingyuan Hong, An Chen, Xiaojia |
author_facet | Nie, Changjun Qin, Xiaohui Li, Xiaoyan Tian, Baoqing Zhao, Ying Jin, Yuan Li, Yadan Wang, Qiang Zeng, Dingyuan Hong, An Chen, Xiaojia |
author_sort | Nie, Changjun |
collection | PubMed |
description | Resistance to platinum-based combination chemotherapy is the main cause of poor prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC). Previously, we showed that CACNA2D3 (voltage-dependent subunit alpha 2 delta 3 of a calcium channel complex) was significantly downregulated and functioned as a tumor suppressor in ESCC, but its role in the chemosensitivity of ESCC to cisplatin remained unknown. Here, we found that the expression of CACNA2D3 was significantly associated with poor platinum response in ESCC patients from the Gene Expression Omnibus database. Overexpression of CACNA2D3 increased sensitivity to cisplatin in ESCC in vitro, whereas knockdown of CACNA2D3 increased cisplatin resistance. CACNA2D3 promoted cisplatin-induced apoptosis by modulating intracellular Ca(2+) stores. In vivo experiments further showed that overexpression of CACNA2D3 enhanced cisplatin anti-tumor effects in a xenograft mouse model. CACNA2D3 overexpression also resulted in the attenuation of PI3K and Akt phosphorylation. Treatment with the PI3K/Akt inhibitor LY294002 restored the chemosensitivity of CACAN2D3-knockdown cells to cisplatin. In conclusion, the results of the current study indicate that CACAN2D3 enhances the chemosensitivity of ESCC to cisplatin via inducing Ca(2+)-mediated apoptosis and suppressing PI3K/Akt pathways. Therefore, regulating the expression of CACNA2D3 is a potential new strategy to increase the efficacy of cisplatin in ESCC patients. |
format | Online Article Text |
id | pubmed-6454090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-64540902019-04-18 CACNA2D3 Enhances the Chemosensitivity of Esophageal Squamous Cell Carcinoma to Cisplatin via Inducing Ca(2+)-Mediated Apoptosis and Suppressing PI3K/Akt Pathways Nie, Changjun Qin, Xiaohui Li, Xiaoyan Tian, Baoqing Zhao, Ying Jin, Yuan Li, Yadan Wang, Qiang Zeng, Dingyuan Hong, An Chen, Xiaojia Front Oncol Oncology Resistance to platinum-based combination chemotherapy is the main cause of poor prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC). Previously, we showed that CACNA2D3 (voltage-dependent subunit alpha 2 delta 3 of a calcium channel complex) was significantly downregulated and functioned as a tumor suppressor in ESCC, but its role in the chemosensitivity of ESCC to cisplatin remained unknown. Here, we found that the expression of CACNA2D3 was significantly associated with poor platinum response in ESCC patients from the Gene Expression Omnibus database. Overexpression of CACNA2D3 increased sensitivity to cisplatin in ESCC in vitro, whereas knockdown of CACNA2D3 increased cisplatin resistance. CACNA2D3 promoted cisplatin-induced apoptosis by modulating intracellular Ca(2+) stores. In vivo experiments further showed that overexpression of CACNA2D3 enhanced cisplatin anti-tumor effects in a xenograft mouse model. CACNA2D3 overexpression also resulted in the attenuation of PI3K and Akt phosphorylation. Treatment with the PI3K/Akt inhibitor LY294002 restored the chemosensitivity of CACAN2D3-knockdown cells to cisplatin. In conclusion, the results of the current study indicate that CACAN2D3 enhances the chemosensitivity of ESCC to cisplatin via inducing Ca(2+)-mediated apoptosis and suppressing PI3K/Akt pathways. Therefore, regulating the expression of CACNA2D3 is a potential new strategy to increase the efficacy of cisplatin in ESCC patients. Frontiers Media S.A. 2019-04-02 /pmc/articles/PMC6454090/ /pubmed/31001468 http://dx.doi.org/10.3389/fonc.2019.00185 Text en Copyright © 2019 Nie, Qin, Li, Tian, Zhao, Jin, Li, Wang, Zeng, Hong and Chen. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Nie, Changjun Qin, Xiaohui Li, Xiaoyan Tian, Baoqing Zhao, Ying Jin, Yuan Li, Yadan Wang, Qiang Zeng, Dingyuan Hong, An Chen, Xiaojia CACNA2D3 Enhances the Chemosensitivity of Esophageal Squamous Cell Carcinoma to Cisplatin via Inducing Ca(2+)-Mediated Apoptosis and Suppressing PI3K/Akt Pathways |
title | CACNA2D3 Enhances the Chemosensitivity of Esophageal Squamous Cell Carcinoma to Cisplatin via Inducing Ca(2+)-Mediated Apoptosis and Suppressing PI3K/Akt Pathways |
title_full | CACNA2D3 Enhances the Chemosensitivity of Esophageal Squamous Cell Carcinoma to Cisplatin via Inducing Ca(2+)-Mediated Apoptosis and Suppressing PI3K/Akt Pathways |
title_fullStr | CACNA2D3 Enhances the Chemosensitivity of Esophageal Squamous Cell Carcinoma to Cisplatin via Inducing Ca(2+)-Mediated Apoptosis and Suppressing PI3K/Akt Pathways |
title_full_unstemmed | CACNA2D3 Enhances the Chemosensitivity of Esophageal Squamous Cell Carcinoma to Cisplatin via Inducing Ca(2+)-Mediated Apoptosis and Suppressing PI3K/Akt Pathways |
title_short | CACNA2D3 Enhances the Chemosensitivity of Esophageal Squamous Cell Carcinoma to Cisplatin via Inducing Ca(2+)-Mediated Apoptosis and Suppressing PI3K/Akt Pathways |
title_sort | cacna2d3 enhances the chemosensitivity of esophageal squamous cell carcinoma to cisplatin via inducing ca(2+)-mediated apoptosis and suppressing pi3k/akt pathways |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454090/ https://www.ncbi.nlm.nih.gov/pubmed/31001468 http://dx.doi.org/10.3389/fonc.2019.00185 |
work_keys_str_mv | AT niechangjun cacna2d3enhancesthechemosensitivityofesophagealsquamouscellcarcinomatocisplatinviainducingca2mediatedapoptosisandsuppressingpi3kaktpathways AT qinxiaohui cacna2d3enhancesthechemosensitivityofesophagealsquamouscellcarcinomatocisplatinviainducingca2mediatedapoptosisandsuppressingpi3kaktpathways AT lixiaoyan cacna2d3enhancesthechemosensitivityofesophagealsquamouscellcarcinomatocisplatinviainducingca2mediatedapoptosisandsuppressingpi3kaktpathways AT tianbaoqing cacna2d3enhancesthechemosensitivityofesophagealsquamouscellcarcinomatocisplatinviainducingca2mediatedapoptosisandsuppressingpi3kaktpathways AT zhaoying cacna2d3enhancesthechemosensitivityofesophagealsquamouscellcarcinomatocisplatinviainducingca2mediatedapoptosisandsuppressingpi3kaktpathways AT jinyuan cacna2d3enhancesthechemosensitivityofesophagealsquamouscellcarcinomatocisplatinviainducingca2mediatedapoptosisandsuppressingpi3kaktpathways AT liyadan cacna2d3enhancesthechemosensitivityofesophagealsquamouscellcarcinomatocisplatinviainducingca2mediatedapoptosisandsuppressingpi3kaktpathways AT wangqiang cacna2d3enhancesthechemosensitivityofesophagealsquamouscellcarcinomatocisplatinviainducingca2mediatedapoptosisandsuppressingpi3kaktpathways AT zengdingyuan cacna2d3enhancesthechemosensitivityofesophagealsquamouscellcarcinomatocisplatinviainducingca2mediatedapoptosisandsuppressingpi3kaktpathways AT hongan cacna2d3enhancesthechemosensitivityofesophagealsquamouscellcarcinomatocisplatinviainducingca2mediatedapoptosisandsuppressingpi3kaktpathways AT chenxiaojia cacna2d3enhancesthechemosensitivityofesophagealsquamouscellcarcinomatocisplatinviainducingca2mediatedapoptosisandsuppressingpi3kaktpathways |