Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference

Ting Chun Kuo, Kuo Yen Huang, Shuenn Chen Yang, Sean Wu, Wei Chia Chung, Yih Leong Chang, Tse Ming Hong, Shu Ping Wang, Hsuan Yu Chen, Tzu Hung Hsiao, Pan Chyr Yang

研究成果: Article

摘要

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.

原文English
頁(從 - 到)189-201
頁數13
期刊Molecular Therapy - Oncolytics
18
DOIs
出版狀態Published - 2020 九月 25

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Pharmacology (medical)

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    Kuo, T. C., Huang, K. Y., Yang, S. C., Wu, S., Chung, W. C., Chang, Y. L., Hong, T. M., Wang, S. P., Chen, H. Y., Hsiao, T. H., & Yang, P. C. (2020). Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference. Molecular Therapy - Oncolytics, 18, 189-201. https://doi.org/10.1016/j.omto.2020.06.012