Chemical dissection of the link between streptozotocin, O-GlcNAc, and pancreatic cell death.
Streptozotocin is a natural product that selectively kills insulin-secreting beta cells, and is widely used to generate mouse models of diabetes or treat pancreatic tumors. Several studies suggest that streptozotocin toxicity stems from its N-nitrosourea moiety releasing nitric oxide and possessing DNA alkylating activity. However, it has also been proposed that streptozotocin induces apoptosis by inhibiting O-GlcNAcase, an enzyme that, together with O-GlcNAc transferase, is important for dynamic intracellular protein O-glycosylation. We have used galacto-streptozotocin to chemically dissect the link between O-GlcNAcase inhibition and apoptosis. Using X-ray crystallography, enzymology, and cell biological studies on an insulinoma cell line, we show that, whereas streptozotocin competitively inhibits O-GlcNAcase and induces apoptosis, its galacto-configured derivative no longer inhibits O-GlcNAcase, yet still induces apoptosis. This supports a general chemical poison mode of action for streptozotocin, suggesting the need for using more specific inhibitors to study protein O-GlcNAcylation.
Pathak
Shalini
S
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, Scotland.
Dorfmueller
Helge C
HC
Borodkin
Vladimir S
VS
van Aalten
Daan M F
DM
D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001667:Binding, Competitive; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects*; D007340:Insulinoma / Q000473:pathology; D051379:Mice; D013311:Streptozocin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D013311:Streptozocin; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine