Glutamine is a substrate for glycosylation and CA19-9 biosynthesis through hexosamine biosynthetic pathway in pancreatic cancer

Chen Liu; Shengming Deng; Zhiwen Xiao; Renquan Lu; He Cheng; Jingjing Feng; Xuxia Shen; Quanxing Ni; Weiding Wu; Xianjun Yu; Guopei Luo

doi:10.1007/s12672-023-00628-z

Glutamine is a substrate for glycosylation and CA19-9 biosynthesis through hexosamine biosynthetic pathway in pancreatic cancer

Discov Oncol. 2023 Feb 17;14(1):20. doi: 10.1007/s12672-023-00628-z.

Authors

Chen Liu^#^{1

2

3

4}, Shengming Deng^#^{1

2

3

4}, Zhiwen Xiao^#^{1

2

3

4}, Renquan Lu^{2

5}, He Cheng^{1

2

3

4}, Jingjing Feng^{2

5}, Xuxia Shen^{2

6}, Quanxing Ni^{1

2

3

4}, Weiding Wu^{1

2

3

4}, Xianjun Yu^{7

8

9

10}, Guopei Luo^{11

12

13

14}

Affiliations

¹ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270,Dong'An Rd, Xuhui District, Shanghai, 200032, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
³ Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
⁴ Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
⁵ Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
⁶ Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
⁷ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270,Dong'An Rd, Xuhui District, Shanghai, 200032, China. [email protected].
⁸ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
⁹ Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. [email protected].
¹⁰ Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China. [email protected].
¹¹ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270,Dong'An Rd, Xuhui District, Shanghai, 200032, China. [email protected].
¹² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
¹³ Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. [email protected].
¹⁴ Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China. [email protected].

^# Contributed equally.

Abstract

Background: Carbohydrate antigen 19-9 (CA19-9) is the most widely used biomarker for pancreatic cancer. Since CA19-9 closely correlates with patient outcome and tumor stage in pancreatic cancer, the deciphering of CA19-9 biosynthesis provides a potential clue for treatment.

Methods: Concentration of amino acids was detected by ultrahigh-performance liquid chromatography tandem mass spectrometry. Metabolic flux of glutamine was examined by isotope tracing untargeted metabolomics. Label-free quantitative N-glycosylation proteomics was used to examine N-glycosylation alterations.

Results: Among all amino acids, glutamine was higher in CA19-9-high pancreatic cancers (> 37 U/mL, 66 cases) than in CA19-9-normal clinical specimens (≤ 37 U/mL, 37 cases). The glutamine concentration in clinical specimens was positively correlated with liver metastasis or lymphovascular invasion. Glutamine blockade using diazooxonorleucine suppressed pancreatic cancer growth and intraperitoneal and lymphatic metastasis. Glutamine promotes O-GlcNAcylation, protein glycosylation, and CA19-9 biosynthesis through the hexosamine biosynthetic pathway. UDP-N-acetylglucosamine (UDP-GlcNAc) levels correlated with the glutamine influx through hexosamine biosynthetic pathway and supported CA19-9 biosynthesis.

Conclusions: Glutamine is a substrate for CA19-9 biosynthesis in pancreatic cancer. Glutamine blockade may be a potential therapeutic strategy for pancreatic cancer.

Keywords: CA19-9; GlcNAc; Glucose; Glutamine; Pancreatic adenocarcinoma.

Abstract

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