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

Linlin Sun1, Xiuju Liu2, Haian Fu3

  • 1Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, P.R. China.

Plos One
|December 30, 2016
PubMed

Insights

The glycolytic inhibitor 2-deoxyglucose (2-DG) suppresses ERK phosphorylation in lung cancer cells via the LKB1/AMPK pathway. This reveals a novel cross-talk between metabolic regulation and cancer signaling.

Area of Science:

  • Cellular metabolism
  • Cancer biology
  • Signal transduction

Background:

  • Tumor cells exhibit aerobic glycolysis (Warburg effect) for ATP production.
  • 2-deoxyglucose (2-DG) is a known glycolytic inhibitor.
  • The precise impact of 2-DG on cellular signaling pathways, particularly ERK, remains unclear.

Purpose of the Study:

  • To investigate the effect of 2-DG on ERK phosphorylation in lung cancer cells.
  • To elucidate the underlying molecular mechanisms, including the role of LKB1 and AMPK.

Main Methods:

  • Time- and dose-dependent analysis of ERK phosphorylation in response to 2-DG.
  • LKB1 knockdown and restoration experiments in lung cancer cells.
  • Assessment of AMPK pathway involvement using inhibitors and siRNA.
  • Investigation of upstream regulators like K-Ras and IGF1.

Main Results:

  • 2-DG inhibits ERK phosphorylation in a time- and dose-dependent manner.
  • This inhibition is dependent on functional Liver Kinase B1 (LKB1).
  • 2-DG-induced ERK inhibition is mediated by the LKB1/AMPK signaling pathway.
  • Insulin-like Growth Factor 1 (IGF1)-induced ERK phosphorylation is reduced by 2-DG.
  • Certain oncogenic K-Ras mutants interfere with 2-DG-mediated LKB1/AMPK signaling.

Conclusions:

  • 2-DG exerts its inhibitory effect on ERK phosphorylation through the LKB1/AMPK pathway.
  • A significant cross-talk exists between LKB1/AMPK metabolic signaling and ERK pathway activation in lung cancer.
  • These findings enhance the understanding of 2-DG's mechanism of action and its potential in cancer therapy.

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