Document Detail


2-Deoxy-D-glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletion.
MedLine Citation:
PMID:  20593179     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: The glucose analog and glycolytic inhibitor 2-deoxy-D-glucose (2-DG), which is currently under clinical evaluation for targeting cancer cells, not only blocks glycolysis thereby reducing cellular ATP, but also interferes with N-linked glycosylation, which leads to endoplasmic reticulum (ER) stress and an unfolded protein response (UPR). Both bioenergetic challenge and ER stress have been shown to activate autophagy, a bulk cellular degradation process that plays either a pro- or anti-death role. Here, we investigate which pathway 2-DG interferes with that activates autophagy and the role of this process in modulating 2-DG-induced toxicity.
METHODS: Pancreatic cancer cell line 1420, melanoma cell line MDA-MB-435 and breast cancer cell line SKBR3 were used to investigate the relationship between induction by 2-DG treatment of ER stress/UPR, ATP reduction and activation of autophagy. ER stress/UPR (Grp78 and CHOP) and autophagy (LC3B II) markers were assayed by immunoblotting, while ATP levels were measured using the CellTiter-Glo Luminescent Cell Viability Assay. Autophagy was also measured by immunofluorescence utilizing LC3B antibody. Cell death was detected with a Vi-Cell cell viability analyzer using trypan blue exclusion.
RESULTS: In the three different cancer cell lines described earlier, we find that 2-DG upregulates autophagy, increases ER stress and lowers ATP levels. Addition of exogenous mannose reverses 2-DG-induced autophagy and ER stress but does not recover the lowered levels of ATP. Moreover, under anaerobic conditions where 2-DG severely depletes ATP, autophagy is diminished rather than activated, which correlates with lowered levels of the ER stress marker Grp78. Additionally, when autophagy is blocked by siRNA, cell sensitivity to 2-DG is increased corresponding with upregulation of ER stress-mediated apoptosis. Similar increased toxicity is observed with 3-methyladenine, a known autophagy inhibitor. In contrast, rapamycin which enhances autophagy reduces 2-DG-induced toxicity.
CONCLUSIONS: Overall, these results indicate that the major mechanism by which 2-DG stimulates autophagy is through ER stress/UPR and not by lowering ATP levels. Furthermore, autophagy plays a protective role against 2-DG-elicited cell death apparently by relieving ER stress. These data suggest that combining autophagy inhibitors with 2-DG may be useful clinically.
Authors:
Haibin Xi; Metin Kurtoglu; Huaping Liu; Medhi Wangpaichitr; Min You; Xiongfei Liu; Niramol Savaraj; Theodore J Lampidis
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-07-01
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  67     ISSN:  1432-0843     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-03-28     Completed Date:  2011-05-23     Revised Date:  2011-07-28    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  899-910     Citation Subset:  IM    
Affiliation:
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, PAP Building, Room 115, 1550 NW 10th Ave, Miami, FL 33136, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Antimetabolites / pharmacology*
Apoptosis / drug effects
Autophagy / drug effects*
Breast Neoplasms / drug therapy,  pathology
Cell Line, Tumor
Cell Survival / drug effects
Deoxyglucose / pharmacology*
Endoplasmic Reticulum / drug effects*,  metabolism
Female
Fluorescent Antibody Technique
Humans
Melanoma / drug therapy,  pathology
Pancreatic Neoplasms / drug therapy,  pathology
Unfolded Protein Response / drug effects
Grant Support
ID/Acronym/Agency:
CA37109/CA/NCI NIH HHS; R01 CA037109-22/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antimetabolites; 154-17-6/Deoxyglucose; 56-65-5/Adenosine Triphosphate
Comments/Corrections

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