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

PloS One
Thomas MühlenbergSebastian Bauer

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 ...Continue Reading

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Citations

Oct 1, 2016·Oncotarget·Camila Rubio-PatiñoJean-Ehrland Ricci
Jul 28, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Ryuji YamaguchiKiichi Hirota
May 11, 2016·Current Opinion in Oncology·Michael PogorzelskiSebastian Bauer
Mar 13, 2018·Frontiers in Immunology·Soumaya KouidhiAmel Benammar Elgaaied
Sep 14, 2019·Clinical and Translational Radiation Oncology·Felix Christian HasseFlorian Sterzing

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Datasets Mentioned

BETA
ABT-263

Methods Mentioned

BETA
Protein Assay
glycosylation
flow cytometry
xenografts
xenograft

Software Mentioned

Modfit LT

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