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PLoS One. 2015 Mar 17;10(3):e0120531. doi: 10.1371/journal.pone.0120531. eCollection 2015.

Inhibition of KIT-glycosylation by 2-deoxyglucose abrogates KIT-signaling and combination with ABT-263 synergistically induces apoptosis in gastrointestinal stromal tumor.

Author information

1
Dept. of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Sarcoma Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
2
Sarcoma Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Dept. of Visceral and Transplant Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
3
Dept. of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
4
Dept. of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

Abstract

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is frequently used for visualizing gastrointestinal stromal tumors (GIST), which are highly glucose-avid tumors. Dramatic metabolic responses following imatinib treatment indicate a high, KIT-dependent glucose turnover which has been particularly helpful for predicting tumor response to imatinib. The glucose analogue 2-deoxyglucose (2DG) inhibits glucose metabolism in cancer cells that depend on aerobic glycolysis for ATP production. We show that 2DG inhibits proliferation in both imatinib-sensitive and imatinib-resistant GIST cell lines at levels that can be achieved clinically. KIT-negative GIST48B have 3-14-fold higher IC50 levels than KIT-positive GIST cells indicating that oncogenic KIT may sensitize cells to 2DG. GIST sensitivity to 2DG is increased in low-glucose media (110 mg/dl). 2DG leads to dose- and glucose dependent inhibition of KIT glycosylation with resultant reduction of membrane-bound KIT, inhibition of KIT-phosphorylation and inactivation of KIT-dependent signaling intermediates. In contrast to imatinib, 2DG caused ER-stress and elicited the unfolded protein response (UPR). Mannose but not pyruvate rescued GIST cells from 2DG-induced growth arrest, suggesting that loss of KIT integrity is the predominant effect of 2DG in GIST. Additive anti-tumoral effects were seen with imatinib and BH3-mimetics. Our data provide the first evidence that modulation of the glucose-metabolism by 2DG may have a disease-specific effect and may be therapeutically useful in GIST.

PMID:
25781619
PMCID:
PMC4364009
DOI:
10.1371/journal.pone.0120531
[Indexed for MEDLINE]
Free PMC Article

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