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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2020
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.
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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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