Chemical dissection of the link between streptozotocin, O-GlcNAc, and pancreatic cell death.

Abstract

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.

• Authors: Shalini Pathak, Helge C Dorfmueller, Vladimir S Borodkin, Daan M F van Aalten
• Journal: Chemistry & biology (Chem Biol) Vol. 15 Issue 8 Pg. 799-807 (Aug 25 2008) ISSN: 1074-5521 [Print] United States
• PMID: 18721751 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Streptozocin
• hexosaminidase C
• beta-N-Acetylhexosaminidases
• Acetylglucosamine

Topics

• Acetylglucosamine (metabolism)
• Animals
• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Apoptosis (drug effects)
• Binding, Competitive
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Insulin-Secreting Cells (cytology, drug effects)
• Insulinoma (pathology)
• Mice
• Streptozocin (chemistry, metabolism, pharmacology)
• beta-N-Acetylhexosaminidases (antagonists & inhibitors, chemistry, metabolism)