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Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells
BACKGROUND: Metabolic reprogramming contributes significantly to tumor development and is tightly linked to drug resistance. The chemotherapeutic agent etoposide (VP-16) has been used clinically in the treatment of lung cancer but possess different sensitivity and efficacy towards SCLC and NSCLC. He...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583203/ https://www.ncbi.nlm.nih.gov/pubmed/33097055 http://dx.doi.org/10.1186/s12964-020-00653-3 |
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author | Dong, Qi Zhou, Chenkang Ren, Haodong Zhang, Zhijian Cheng, Feng Xiong, Zhenkai Chen, Chuantao Yang, Jianke Gao, Jiguang Zhang, Yao Xu, Lei Fang, Jian Cao, Yuxiang Wei, Huijun Wu, Zhihao |
author_facet | Dong, Qi Zhou, Chenkang Ren, Haodong Zhang, Zhijian Cheng, Feng Xiong, Zhenkai Chen, Chuantao Yang, Jianke Gao, Jiguang Zhang, Yao Xu, Lei Fang, Jian Cao, Yuxiang Wei, Huijun Wu, Zhihao |
author_sort | Dong, Qi |
collection | PubMed |
description | BACKGROUND: Metabolic reprogramming contributes significantly to tumor development and is tightly linked to drug resistance. The chemotherapeutic agent etoposide (VP-16) has been used clinically in the treatment of lung cancer but possess different sensitivity and efficacy towards SCLC and NSCLC. Here, we assessed the impact of etoposide on glycolytic metabolism in SCLC and NSCLC cell lines and investigated the role of metabolic rewiring in mediating etoposide resistance. METHODS: glycolytic differences of drug-treated cancer cells were determined by extracellular acidification rate (ECAR), glucose consumption, lactate production and western blot. DNA damage was evaluated by the comet assay and western blot. Chemoresistant cancer cells were analyzed by viability, apoptosis and western blot. Chromatin immunoprecipitation (ChIP) was used for analysis of DNA-protein interaction. RESULTS: Here we showed that exposure to chemotherapeutic drug etoposide induces an exacerbation of ROS production which activates HIF-1α-mediated the metabolic reprogramming toward increased glycolysis and lactate production in non-small cell lung cancer (NSCLC). We identified lactic acidosis as the key that confers multidrug resistance through upregulation of multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1), a member of ATP-binding cassette (ABC) transporter family. Mechanistically, lactic acid coordinates TGF-β1/Snail and TAZ/AP-1 pathway to induce formation of Snail/TAZ/AP-1 complex at the MRP1/ABCC1 promoter. Induction of MRP1 expression inhibits genotoxic and apoptotic effects of chemotherapeutic drugs by increasing drug efflux. Furthermore, titration of lactic acid with NaHCO(3) was sufficient to overcome resistance. CONCLUSIONS: The chemotherapeutic drug etoposide induces the shift toward aerobic glycolysis in the NSCLC rather than SCLC cell lines. The increased lactic acid in extracellular environment plays important role in etoposide resistance through upregulation of MRP expression. These data provide first evidence for the increased lactate production, upon drug treatment, contributes to adaptive resistance in NSCLC and reveal potential vulnerabilities of lactate metabolism and/or pathway suitable for therapeutic targeting. GRAPHICAL ABSTRACT: [Figure: see text] |
format | Online Article Text |
id | pubmed-7583203 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-75832032020-10-26 Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells Dong, Qi Zhou, Chenkang Ren, Haodong Zhang, Zhijian Cheng, Feng Xiong, Zhenkai Chen, Chuantao Yang, Jianke Gao, Jiguang Zhang, Yao Xu, Lei Fang, Jian Cao, Yuxiang Wei, Huijun Wu, Zhihao Cell Commun Signal Research BACKGROUND: Metabolic reprogramming contributes significantly to tumor development and is tightly linked to drug resistance. The chemotherapeutic agent etoposide (VP-16) has been used clinically in the treatment of lung cancer but possess different sensitivity and efficacy towards SCLC and NSCLC. Here, we assessed the impact of etoposide on glycolytic metabolism in SCLC and NSCLC cell lines and investigated the role of metabolic rewiring in mediating etoposide resistance. METHODS: glycolytic differences of drug-treated cancer cells were determined by extracellular acidification rate (ECAR), glucose consumption, lactate production and western blot. DNA damage was evaluated by the comet assay and western blot. Chemoresistant cancer cells were analyzed by viability, apoptosis and western blot. Chromatin immunoprecipitation (ChIP) was used for analysis of DNA-protein interaction. RESULTS: Here we showed that exposure to chemotherapeutic drug etoposide induces an exacerbation of ROS production which activates HIF-1α-mediated the metabolic reprogramming toward increased glycolysis and lactate production in non-small cell lung cancer (NSCLC). We identified lactic acidosis as the key that confers multidrug resistance through upregulation of multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1), a member of ATP-binding cassette (ABC) transporter family. Mechanistically, lactic acid coordinates TGF-β1/Snail and TAZ/AP-1 pathway to induce formation of Snail/TAZ/AP-1 complex at the MRP1/ABCC1 promoter. Induction of MRP1 expression inhibits genotoxic and apoptotic effects of chemotherapeutic drugs by increasing drug efflux. Furthermore, titration of lactic acid with NaHCO(3) was sufficient to overcome resistance. CONCLUSIONS: The chemotherapeutic drug etoposide induces the shift toward aerobic glycolysis in the NSCLC rather than SCLC cell lines. The increased lactic acid in extracellular environment plays important role in etoposide resistance through upregulation of MRP expression. These data provide first evidence for the increased lactate production, upon drug treatment, contributes to adaptive resistance in NSCLC and reveal potential vulnerabilities of lactate metabolism and/or pathway suitable for therapeutic targeting. GRAPHICAL ABSTRACT: [Figure: see text] BioMed Central 2020-10-23 /pmc/articles/PMC7583203/ /pubmed/33097055 http://dx.doi.org/10.1186/s12964-020-00653-3 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Dong, Qi Zhou, Chenkang Ren, Haodong Zhang, Zhijian Cheng, Feng Xiong, Zhenkai Chen, Chuantao Yang, Jianke Gao, Jiguang Zhang, Yao Xu, Lei Fang, Jian Cao, Yuxiang Wei, Huijun Wu, Zhihao Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells |
title | Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells |
title_full | Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells |
title_fullStr | Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells |
title_full_unstemmed | Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells |
title_short | Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells |
title_sort | lactate-induced mrp1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583203/ https://www.ncbi.nlm.nih.gov/pubmed/33097055 http://dx.doi.org/10.1186/s12964-020-00653-3 |
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