A common sugar-nucleotide-mediated mechanism of inhibition of (glycosamino) glycan biosynthesis, as evidenced by 6F-GalNAc (Ac-3)

作者：van Wijk Xander M; Lawrence Roger; Thijssen Victor L; van den Broek Sebastiaan A; Troost Ran; van Scherpenzeel Monique; Naidu Natasha; Oosterhof Arie; Griffioen Arjan W; Lefeber Dirk J; van Delft Floris L; van Kuppevelt Toin H^*

来源：The FASEB Journal, 2015, 29(7): 2993-3002.

DOI：10.1096/fj.14-264226

• sugar analog
• angiogenesis
• growth factor signaling
• glycobiology

Glycosaminoglycan (GAG) polysaccharides have been implicated in a variety of cellular processes, and alterations in their amount and structure have been associated with diseases such as cancer. In this study, we probed 11 sugar analogs for their capacity to interfere with GAG biosynthesis. One analog, with a modification not directly involved in the glycosidic bond formation, 6F-N-acetyl-D-galactosamine (GalNAc) (Ac-3), was selected for further study on its metabolic and biologic effect. Treatment of human ovarian carcinoma cells with 50 mM 6F-GalNAc (Ac-3) inhibited biosynthesis of GAGs (chondroitin/dermatan sulfate by similar to 50-60%, heparan sulfate by similar to 35%), N-acetyl-D-glucosamine (GlcNAc)/GalNAc containing glycans recognized by the lectins Datura stramonium and peanut agglutinin (by similar to 74 and similar to 43%, respectively), and O-GlcNAc protein modification. With respect to function, 6F-GalNAc (Ac-3) treatment inhibited growth factor signaling and reduced in vivo angiogenesis by similar to 33%. Although the analog was readily transformed in cells into the uridine 59-diphosphate (UDP)-activated form, it was not incorporated into GAGs. Rather, it strongly reduced cellular UDP-GalNAc and UDP-GlcNAc pools. Together with data from the literature, these findings indicate that nucleotide sugar depletion without incorporation is a common mechanism of sugar analogs for inhibiting GAG/glycan biosynthesis.

• 出版日期2015-7