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The glycolytic inhibitor 2-deoxyglucose activates multiple prosurvival pathways through IGF1R

Diansheng Zhong1, Li Xiong, Tongrui Liu

  • 1Department of Hematology, Emory University, Atlanta, Georgia 30322, USA.

The Journal of Biological Chemistry
|July 4, 2009
PubMed

Insights

2-deoxyglucose (2-DG) activates cancer cell survival pathways via insulin-like growth factor 1 receptor (IGF1R) signaling. Inhibiting IGF1R alongside 2-DG significantly reduces tumor cell proliferation and promotes apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Aerobic glycolysis is crucial in tumorigenesis and a target for cancer therapy.
  • 2-deoxyglucose (2-DG), a known glycolytic inhibitor, unexpectedly activates prosurvival pathways like PI3K/AKT.
  • The interaction between insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP3) is implicated in cancer cell survival.

Purpose of the Study:

  • To investigate the mechanism by which 2-DG activates prosurvival signaling pathways.
  • To determine if IGF-1 receptor (IGF1R) signaling is involved in 2-DG-mediated activation of cancer cell survival.
  • To evaluate the therapeutic potential of combining 2-DG with IGF1R inhibition.

Main Methods:

  • Utilized phospho-specific antibody microarray analysis to identify 2-DG-regulated signaling pathways.
  • Investigated the effect of 2-DG on the IGF-1/IGFBP3 complex and subsequent IGF1R activation.
  • Employed chemical inhibition of IGF1R to assess its role in 2-DG-induced signaling.
  • Performed in vitro studies combining subtoxic doses of 2-DG and an IGF1R inhibitor.

Main Results:

  • 2-DG treatment disrupts the IGF-1/IGFBP3 complex, releasing free IGF-1 and activating IGF1R signaling.
  • IGF1R activation by 2-DG leads to the induction of MEK-ERK signaling in cancer cells.
  • 2-DG up-regulates phosphorylation at 64 sites across various signaling pathways; IGF1R inhibition reduces 57 of these.
  • Combined treatment with 2-DG and an IGF1R inhibitor reduced cancer cell proliferation by 90% and induced significant apoptosis.

Conclusions:

  • 2-DG activates multiple cancer cell survival pathways, including PI3K/AKT and MEK-ERK, primarily through IGF1R signaling.
  • Inhibition of IGF1R can effectively attenuate 2-DG-induced prosurvival signaling.
  • Combining subtoxic doses of 2-DG with IGF1R inhibition presents a promising therapeutic strategy against cancer.

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