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Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference
Targeting metabolic reprogramming is an emerging strategy in cancer therapy. However, clinical attempts to target metabolic reprogramming have been proved to be challenging, with metabolic heterogeneity of cancer being one of many reasons that causes treatment failure. Here, we stratified non-small...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364124/ https://www.ncbi.nlm.nih.gov/pubmed/32695876 http://dx.doi.org/10.1016/j.omto.2020.06.012 |
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author | Kuo, Ting-Chun Huang, Kuo-Yen Yang, Shuenn-Chen Wu, Sean Chung, Wei-Chia Chang, Yih-Leong Hong, Tse-Ming Wang, Shu-Ping Chen, Hsuan-Yu Hsiao, Tzu-Hung Yang, Pan-Chyr |
author_facet | Kuo, Ting-Chun Huang, Kuo-Yen Yang, Shuenn-Chen Wu, Sean Chung, Wei-Chia Chang, Yih-Leong Hong, Tse-Ming Wang, Shu-Ping Chen, Hsuan-Yu Hsiao, Tzu-Hung Yang, Pan-Chyr |
author_sort | Kuo, Ting-Chun |
collection | PubMed |
description | Targeting metabolic reprogramming is an emerging strategy in cancer therapy. However, clinical attempts to target metabolic reprogramming have been proved to be challenging, with metabolic heterogeneity of cancer being one of many reasons that causes treatment failure. Here, we stratified non-small cell lung cancer (NSCLC) cells, mainly lung adenocarcinoma, based on their metabolic phenotypes and demonstrated that the aerobic glycolysis-preference NSCLC cell subtype was resistant to the OXPHOS-targeting inhibitors. We identified that monocarboxylate transporter 4 (MCT4), a lactate transporter, was highly expressed in the aerobic glycolysis-preference subtype with function supporting the proliferation of these cells. Glucose could induce the expression of MCT4 in these cells through a ΔNp63α and Sp1-dependent pathway. Next, we showed that knockdown of MCT4 increased intracellular lactate concentration and induced a reactive oxygen species (ROS)-dependent cellular apoptosis in the aerobic glycolysis-preference NSCLC cell subtype. By scanning a panel of monoclonal antibodies with MCT4 neutralizing activity, we further identified a MCT4 immunoglobulin M (IgM) monoclonal antibody showing capable anti-proliferation efficacy on the aerobic glycolysis-preference NSCLC cell subtype. Our findings indicate that the metabolic heterogeneity is a critical factor for NSCLC therapy and manipulating the expression or function of MCT4 can be an effective strategy in targeting the aerobic glycolysis-preference NSCLC cell subtype. |
format | Online Article Text |
id | pubmed-7364124 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-73641242020-07-20 Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference Kuo, Ting-Chun Huang, Kuo-Yen Yang, Shuenn-Chen Wu, Sean Chung, Wei-Chia Chang, Yih-Leong Hong, Tse-Ming Wang, Shu-Ping Chen, Hsuan-Yu Hsiao, Tzu-Hung Yang, Pan-Chyr Mol Ther Oncolytics Article Targeting metabolic reprogramming is an emerging strategy in cancer therapy. However, clinical attempts to target metabolic reprogramming have been proved to be challenging, with metabolic heterogeneity of cancer being one of many reasons that causes treatment failure. Here, we stratified non-small cell lung cancer (NSCLC) cells, mainly lung adenocarcinoma, based on their metabolic phenotypes and demonstrated that the aerobic glycolysis-preference NSCLC cell subtype was resistant to the OXPHOS-targeting inhibitors. We identified that monocarboxylate transporter 4 (MCT4), a lactate transporter, was highly expressed in the aerobic glycolysis-preference subtype with function supporting the proliferation of these cells. Glucose could induce the expression of MCT4 in these cells through a ΔNp63α and Sp1-dependent pathway. Next, we showed that knockdown of MCT4 increased intracellular lactate concentration and induced a reactive oxygen species (ROS)-dependent cellular apoptosis in the aerobic glycolysis-preference NSCLC cell subtype. By scanning a panel of monoclonal antibodies with MCT4 neutralizing activity, we further identified a MCT4 immunoglobulin M (IgM) monoclonal antibody showing capable anti-proliferation efficacy on the aerobic glycolysis-preference NSCLC cell subtype. Our findings indicate that the metabolic heterogeneity is a critical factor for NSCLC therapy and manipulating the expression or function of MCT4 can be an effective strategy in targeting the aerobic glycolysis-preference NSCLC cell subtype. American Society of Gene & Cell Therapy 2020-06-24 /pmc/articles/PMC7364124/ /pubmed/32695876 http://dx.doi.org/10.1016/j.omto.2020.06.012 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Kuo, Ting-Chun Huang, Kuo-Yen Yang, Shuenn-Chen Wu, Sean Chung, Wei-Chia Chang, Yih-Leong Hong, Tse-Ming Wang, Shu-Ping Chen, Hsuan-Yu Hsiao, Tzu-Hung Yang, Pan-Chyr Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference |
title | Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference |
title_full | Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference |
title_fullStr | Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference |
title_full_unstemmed | Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference |
title_short | Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference |
title_sort | monocarboxylate transporter 4 is a therapeutic target in non-small cell lung cancer with aerobic glycolysis preference |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364124/ https://www.ncbi.nlm.nih.gov/pubmed/32695876 http://dx.doi.org/10.1016/j.omto.2020.06.012 |
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