| 2-Deoxy-D-glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletion. | |
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MedLine Citation:
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PMID: 20593179 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Haibin Xi; Metin Kurtoglu; Huaping Liu; Medhi Wangpaichitr; Min You; Xiongfei Liu; Niramol Savaraj; Theodore J Lampidis |
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Publication Detail:
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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:
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Title: Cancer chemotherapy and pharmacology Volume: 67 ISSN: 1432-0843 ISO Abbreviation: Cancer Chemother. Pharmacol. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-03-28 Completed Date: 2011-05-23 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 7806519 Medline TA: Cancer Chemother Pharmacol Country: Germany |
Other Details:
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Languages: eng Pagination: 899-910 Citation Subset: IM |
Affiliation:
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Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, PAP Building, Room 115, 1550 NW 10th Ave, Miami, FL 33136, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate
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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:
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CA37109/CA/NCI NIH HHS; R01 CA037109-22/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antimetabolites; 154-17-6/Deoxyglucose; 56-65-5/Adenosine Triphosphate |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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