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Conversion of 2-deoxyglucose-induced growth inhibition to cell death in normoxic tumor cells
Huaping Liu1, Metin Kurtoglu, Yenong Cao
1Department of Cell Biology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA. HLiu2@med.miami.edu
Background:
Inhibition of glucose metabolism has recently become an attractive target for cancer treatment. Accordingly, since 2-deoxyglucose (2-DG) competes effectively with glucose, it has come under increasing scrutiny as a therapeutic agent. The initial response of tumor cells to 2-DG is growth inhibition, which is thought to conserve energy and consequently protect cells from its ATP-lowering effects as a glycolytic inhibitor. However, since 2-DG also mimics mannose and thereby interferes with N-linked glycosylation, the question is raised of how this sugar analog inhibits tumor cell growth and whether the mechanism by which it protects cells can be manipulated to convert 2-DG-induced growth inhibition to cell death.
Methods:
Cell growth and death were measured via counting viable and dead cells based on trypan blue exclusion. Markers of ATP reduction and the unfolded protein response (UPR) were detected by Western blot. Protein functions were manipulated through chemical compounds, siRNA and the use of gene-specific wild-type and knock-out mouse embryonic fibroblasts (MEFs).
Results:
At 2-DG concentrations that can be achieved in human plasma without causing significant side effects, we find (a) It induces growth inhibition predominantly by interference with glycosylation, which leads to accumulation of unfolded proteins in the endoplasmic reticulum activating the UPR; (b) Inhibition of PERK (but not ATF6 or IRE1), a major component of the UPR, leads to conversion of 2-DG-induced growth inhibition to cell death and (c) secondarily to PERK, inhibition of GCN2, a kinase that is activated in response to low intracellular glutamine, increases 2-DG's cytotoxic effects in PERK -/- MEFs.
Conclusions:
Overall, these findings present a novel anticancer strategy that can be translated into therapeutic gain as they uncover the metabolic target PERK, and to a lesser degree GCN2, that when inhibited convert 2-DG's static effect to a toxic one in tumor cells growing under normoxia.
Insights
This study reveals that inhibiting PERK and GCN2 converts 2-deoxyglucose (2-DG) cancer therapy from growth inhibition to cell death. Targeting these metabolic pathways offers a novel anticancer strategy for tumor cells under normoxia.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Glucose metabolism inhibition is a promising cancer treatment strategy.
- 2-deoxyglucose (2-DG) is investigated as a therapeutic agent due to its competition with glucose.
- 2-DG's mechanism involves growth inhibition via ATP reduction and N-linked glycosylation interference.
Purpose of the Study:
- To elucidate the mechanism by which 2-DG inhibits tumor cell growth.
- To determine if 2-DG's protective effects can be manipulated to induce cell death.
- To identify therapeutic targets for converting 2-DG-induced growth inhibition into cancer cell death.
Main Methods:
- Cell viability and death were assessed using trypan blue exclusion.
- Western blotting was employed to detect ATP reduction and unfolded protein response (UPR) markers.
- Gene function was modulated using chemical inhibitors, siRNA, and gene-specific knockout mouse embryonic fibroblasts (MEFs).
Main Results:
- 2-DG at achievable plasma concentrations inhibits growth by interfering with glycosylation, causing ER stress and activating the UPR.
- Inhibition of PERK, a key UPR component, transforms 2-DG-induced growth inhibition into cell death.
- Inhibition of GCN2, activated by low glutamine, enhances 2-DG's cytotoxicity in PERK-deficient cells.
Conclusions:
- PERK and GCN2 are identified as metabolic targets that can convert 2-DG's static effect to a toxic one in tumor cells.
- This research presents a novel anticancer strategy targeting PERK and GCN2 for therapeutic gain.
- The findings are relevant for developing new cancer therapies for tumor cells under normoxia.
