@article{be0beda175af4e0ca61944acbee9a87b,
title = "Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference",
abstract = "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.",
author = "Kuo, {Ting Chun} and Huang, {Kuo Yen} and Yang, {Shuenn Chen} and Sean Wu and Chung, {Wei Chia} and Chang, {Yih Leong} and Hong, {Tse Ming} and Wang, {Shu Ping} and Chen, {Hsuan Yu} and Hsiao, {Tzu Hung} and Yang, {Pan Chyr}",
note = "Funding Information: We are grateful for the technical service support from the Experimental Animal Facility and DNA Sequencing Laboratory (Institute of Biomedical Sciences, Academia Sinica) and the support of bioinformatics work and computational and storage resources from the Mathematics in Biology Group (Institute of Statistical Science, Academia Sinica) and National Center for High-Performance Computing of National Applied Research Laboratories in Taiwan. Additionally, we thank Dr. Yidong Chen (Graduate School of Biomedical Sciences, University of Texas Health Science Center at San Antonio) for using TRANSFAC database to predict the potential TFs in regulating the expression of MCT4. This research was supported by grants from Ministry of Science and Technology ( MOST-106-2314-B-002-103-MY2 , MOST-107-0210-01-19-01 , MOST-107-2314-B-002-239 , MOST-108-3114-Y-001-002 , MOST-108-2314-B-002-195 , MOST-108-2314-B-002-027 , MOST-108-2320-B-001-007-MY2 , MOST-108-2319-B-492-001 , and MOST-109-0210-01-18-02 ) and Academia Sinica ( AS-SUMMIT-109 and AS-KPQ-109-BioMed ) in Taiwan. Funding Information: We are grateful for the technical service support from the Experimental Animal Facility and DNA Sequencing Laboratory (Institute of Biomedical Sciences, Academia Sinica) and the support of bioinformatics work and computational and storage resources from the Mathematics in Biology Group (Institute of Statistical Science, Academia Sinica) and National Center for High-Performance Computing of National Applied Research Laboratories in Taiwan. Additionally, we thank Dr. Yidong Chen (Graduate School of Biomedical Sciences, University of Texas Health Science Center at San Antonio) for using TRANSFAC database to predict the potential TFs in regulating the expression of MCT4. This research was supported by grants from Ministry of Science and Technology (MOST-106-2314-B-002-103-MY2, MOST-107-0210-01-19-01, MOST-107-2314-B-002-239, MOST-108-3114-Y-001-002, MOST-108-2314-B-002-195, MOST-108-2314-B-002-027, MOST-108-2320-B-001-007-MY2, MOST-108-2319-B-492-001, and MOST-109-0210-01-18-02) and Academia Sinica (AS-SUMMIT-109 and AS-KPQ-109-BioMed) in Taiwan. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = sep,
day = "25",
doi = "10.1016/j.omto.2020.06.012",
language = "English",
volume = "18",
pages = "189--201",
journal = "Molecular Therapy - Oncolytics",
issn = "2372-7705",
publisher = "Nature Publishing Group",
}