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.
Highlights
One of the primary hallmarks of cancer [1] is altered glucose metabolism
We report that 2-DG inhibits the Extracellular signal-regulated kinase (ERK) cascade in a subset of non-small cell lung cancer (NSCLC) cancer cells with wild-type LKB1 and K-Ras
We demonstrate that LKB1 negatively regulates ERK activation in NSCLC cells
Summary
One of the primary hallmarks of cancer [1] is altered glucose metabolism. Tumor cells are known to ferment glucose to lactate in the presence of oxygen, i.e. “aerobic glycolysis” [2]. This process, known as the “Warburg Effect”, is proposed to benefit the growth and survival of cancer cells through several candidate mechanisms [3], including rapid production of ATP [4], promoting biosynthesis [5] and acidification of the tumor microenvironment [6], etc. Based on these mechanistic rationales, targeting glycolysis has been explored as a therapeutic approach for cancer treatment. Our findings uncover the potential cross-talk between LKB1/ AMPK and ERK signaling and offer novel insights into the mechanism of action of 2-DG
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