2-Deoxyglucose Suppresses ERK Phosphorylation in LKB1 and Ras Wild-Type Non-Small Cell Lung Cancer Cells

• Type of Material: Article
• Authors: Linlin Sun, Tianjin Medical University; Xiuju Liu, Emory University; Haian Fu, Emory University; Wei Zhou, Emory University; Diansheng Zhong, Tianjin Medical University
• Language: English
• Date: 2016-12-29
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Sun et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0168793
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 11
• Issue: 12
• Start Page: e0168793
• End Page: e0168793
• Grant/Funding Information: Natural Science Foundation of Tianjin City 16JCYBJC24400 to Linlin Sun.; “New Century” Talent Foundation of Tianjin Medical University General Hospital (2014) to Linlin Sun.; Foundation for the National Institutes of Health R01-CA140571 to Wei Zhou.; Foundation for the National Institutes of Health 5P30CA138292 to Haian Fu.; China Scholarship Council to Linlin Sun.; This work was supported by National Natural Science Foundation of China (No. 81572268 and 81071915 to DZ and No. 31301160 to LS), National Institutes of Health (R01-CA140571 to WZ, P01 CA116676 to HF and WZ), Natural Science Foundation of Tianjin City (No. 16JCYBJC24400 to LS), Winship Cancer Institute (NIH 5P30CA138292 to HF), Anise McDaniel Brock Scholar fund to WZ, China Scholarship Council, and the “New Century” Talent Foundation of Tianjin Medical University General Hospital to LS.; National Natural Science Foundation of China 31301160 to Linlin Sun.; National Natural Science Foundation of China (CN) 81572268 to Diansheng Zhong.; Foundation for the National Institutes of Health P01 CA116676 to Wei Zhou.
• Keywords: Lung and intrathoracic tumors; GROWTH; ADENOCARCINOMA; RADIOTHERAPY; Glycolysis; Science & Technology; MTOR ACTIVITY; 2-DEOXY-D-GLUCOSE; METABOLISM; PROLIFERATION; PATHWAYS; Small interfering RNAs; Multidisciplinary Sciences; GLYCOLYSIS INHIBITION; Non-small cell lung cancer (NSCLC); Science & Technology - Other Topics; ACTIVATED PROTEIN-KINASE
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology; Biology, Genetics

Abstract

Tumor cells rely on aerobic glycolysis to generate ATP, namely the "Warburg" effect. 2-deoxyglucose (2-DG) is well characterized as a glycolytic inhibitor, but its effect on cellular signaling pathways has not been fully elucidated. Herein, we sought to investigate the effect of 2-DG on ERK function in lung cancer cells. We found that 2-DG inhibits ERK phosphorylation in a time and dose-dependent manner in lung cancer cells. This inhibition requires functional LKB1. LKB1 knockdown in LKB1 wildtype cells correlated with an increase in the basal level of p-ERK. Restoration of LKB1 in LKB1-null cells significantly inhibits ERK activation. Blocking AMPK function with AMPK inhibitor, AMPK siRNA or DN-AMPK diminishes the inhibitory effect of 2-DG on ERK, suggesting that 2-DG - induced ERK inhibition is mediated by LKB1/AMPK signaling. Moreover, IGF1-induced ERK phosphorylation is significantly decreased by 2-DG. Conversely, a subset of oncogenic mutants of K-Ras, the main upstream regulator of ERK, blocks 2-DG - induced LKB1/AMPK signaling. These findings reveal the potential cross-talk between LKB1/AMPK and ERK signaling and help to better understand the mechanism of action of 2-DG.