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World J Gastrointest Oncol. Nov 15, 2023; 15(11): 1852-1863
Published online Nov 15, 2023. doi: 10.4251/wjgo.v15.i11.1852
Glutamine addiction and therapeutic strategies in pancreatic cancer
Lin-Lin Ren, Tao Mao, Pin Meng, Li Zhang, Hong-Yun Wei, Zi-Bin Tian
Lin-Lin Ren, Tao Mao, Pin Meng, Hong-Yun Wei, Zi-Bin Tian, Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
Li Zhang, Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
Author contributions: Ren LL wrote the manuscript; Ren LL, Meng P, Zhang L and Wei HY performed the literature retrieval; Tian ZB and Mao T revised the manuscript; all authors have read and approve the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81602056 and No. 82273393; the Natural Science Foundation of Shandong Province, No. ZR2016HQ45 and No. ZR2020LZL004; and the Shandong Traditional Chinese Medicine Science and Technology Project, No. 2021M161.
Conflict-of-interest statement: The authors declare no conflict of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Tao Mao, Doctor, MD, PhD, Associate Chief Physician, Doctor, Teacher, Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266000, Shandong Province, China. maotao@qdu.edu.cn
Received: June 27, 2023
Peer-review started: June 27, 2023
First decision: August 25, 2023
Revised: September 6, 2023
Accepted: October 23, 2023
Article in press: October 23, 2023
Published online: November 15, 2023
Processing time: 141 Days and 7.6 Hours
Abstract

Pancreatic cancer remains one of the most lethal diseases worldwide owing to its late diagnosis, early metastasis, and poor prognosis. Because current therapeutic options are limited, there is an urgent need to investigate novel targeted treatment strategies. Pancreatic cancer faces significant metabolic challenges, principally hypoxia and nutrient deprivation, due to specific microenvironmental constraints, including an extensive desmoplastic stromal reaction. Pancreatic cancer cells have been shown to rewire their metabolism and energy production networks to support rapid survival and proliferation. Increased glucose uptake and glycolytic pathway activity during this process have been extensively described. However, growing evidence suggests that pancreatic cancer cells are glutamine addicted. As a nitrogen source, glutamine directly (or indirectly via glutamate conversion) contributes to many anabolic processes in pancreatic cancer, including amino acids, nucleobases, and hexosamine biosynthesis. It also plays an important role in redox homeostasis, and when converted to α-ketoglutarate, glutamine serves as an energy and anaplerotic carbon source, replenishing the tricarboxylic acid cycle intermediates. The present study aims to provide a comprehensive overview of glutamine metabolic reprogramming in pancreatic cancer, focusing on potential therapeutic approaches targeting glutamine metabolism in pancreatic cancer.

Keywords: Pancreatic cancer; Glutamine metabolism; Cancer treatment; Therapeutic strategies

Core Tip: Most pancreatic ductal adenocarcinomas (PDAC) are diagnosed at an advanced stage, missing the opportunity for surgical treatment and responding poorly to radiotherapy and targeted therapies. Glutamine is a non-essential amino acid that is found in high levels in normal humans. Glutamine metabolism could provide raw material for the synthesis of important molecules and meet the needs of rapid growth and proliferation of tumor cells. The study of glutamine metabolic pathways targeting PDAC may provide new strategies for pancreatic cancer treatment.