作者
Peter K Kim, Christopher J Halbrook, Samuel A Kerk, Megan Radyk, Stephanie Wisner, Daniel M Kremer, Peter Sajjakulnukit, Anthony Andren, Sean W Hou, Ayush Trivedi, Galloway Thurston, Abhinav Anand, Liang Yan, Lucia Salamanca-Cardona, Samuel D Welling, Li Zhang, Matthew R Pratt, Kayvan R Keshari, Haoqiang Ying, Costas A Lyssiotis
发表日期
2021/12/24
期刊
Elife
卷号
10
页码范围
e62645
出版商
eLife Sciences Publications, Ltd
简介
Rewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in human PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not preclude the growth of human tumor xenografts in mice, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. We found that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.
引用总数
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PK Kim, CJ Halbrook, SA Kerk, M Radyk, S Wisner… - Elife, 2021