TY - JOUR
T1 - Glutamine synthetase regulates the immune micro-environment and cancer development through the inflammatory pathway
AU - Xuan, Do Thi Minh
AU - Wu, Chung Che
AU - Wang, Wei Jan
AU - Hsu, Hui Ping
AU - Ta, Hoang Dang Khoa
AU - Anuraga, Gangga
AU - Chiao, Chung Chieh
AU - Wang, Chih Yang
N1 - Funding Information:
This research was supported by grants from the Ministry of Science and Technology (MOST) of Taiwan (MOST-110-2320-B-039-068 to W.J.W., 109-2314-B-006-018-MY3 to H.P.H, and 109-2320-B-038-009-MY2 to C.Y.W.), from Taipei Medical University Hospital (109TMU-TMUH-19, and 111TMU-TMUH-08), from National Cheng Kung University Hospital (NCKUH-10902031 & NCKUH-11002013 & NCKUH-11102007 to H.P.H.). This work was financially supported of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan (DP2-111-21121-01-C-01-01). The authors truly appreciate Mr. Daniel P. Chamberlin from the Office of Research and Development at Taipei Medical University for professional English editing. The authors acknowledge the statistical/computational/technical support of the Clinical Data Center, Office of Data Science, Taipei Medical University, Taiwan.
Funding Information:
This research was supported by grants from the Ministry of Science and Technology (MOST) of Taiwan (MOST-110-2320-B-039-068 to W.J.W., 109-2314-B-006-018-MY3 to H.P.H, and 109-2320-B-038-009-MY2 to C.Y.W.), from Taipei Medical University Hospital (109TMU-TMUH-19, and 111TMU-TMUH-08), from National Cheng Kung University Hospital (NCKUH-10902031 & NCKUH-11002013 & NCKUH-11102007 to H.P.H.). This work was financially supported of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan (DP2-111-21121-01-C-01-01). The authors truly appreciate Mr. Daniel P. Chamberlin from the Office of Research and Development at Taipei Medical University for professional English editing. The authors acknowledge the statistical/computa-tional/technical support of the Clinical Data Center, Office of Data Science, Taipei Medical University, Taiwan.
Publisher Copyright:
© The author(s).
PY - 2023
Y1 - 2023
N2 - Although adjuvant tamoxifen therapy is beneficial to estrogen receptor-positive (ER+) breast cancer patients, a significant number of patients still develop metastasis or undergo recurrence. Therefore, identifying novel diagnostic and prognostic biomarkers for these patients is urgently needed. Predictive markers and therapeutic strategies for tamoxifen-resistant ER+ breast cancer are not clear, and micro (mi)RNAs have recently become a focal research point in cancer studies owing to their regulation of gene expressions, metabolism, and many other physiological processes. Therefore, systematic investigation is required to understand the modulation of gene expression in tamoxifen-resistant patients. High-throughput technology uses a holistic approach to observe differences among expression profiles of thousands of genes, which provides a comprehensive level to extensively investigate functional genomics and biological processes. Through a bioinformatics analysis, we revealed that glutamine synthetase/glutamate-ammonia ligase (GLUL) might play essential roles in the recurrence of tamoxifen-resistant ER+ patients. GLUL increases intracellular glutamine usage via glutaminolysis, and further active metabolism-related downstream molecules in cancer cell. However, how GLUL regulates tumor immunology for tamoxifen-resistant ER+ breast cancer remains unexplored. Analysis of MetaCore pathway database demonstrated that GLUL is involved in the cell cycle, immune response, interleukin (IL)-4-induced regulators of cell growth, differentiation, and metabolism-related pathways. Experimental data also confirmed that the knockdown of GLUL in breast cancer cell lines decreased cell proliferation and influenced expressions of downstream molecules. Through a Connectivity Map (CMap) analysis, we revealed that certain drugs/molecules, including omeprazole, methacholine chloride, ioversol, fulvestrant, difenidol, cycloserine, and MK-801, may serve as potential treatments for tamoxifen-resistant breast cancer patients. These drugs may be tested in combination with current therapies in tamoxifen-resistant breast cancer patients. Collectively, our study demonstrated the crucial roles of GLUL, which provide new targets for the treatment of tamoxifen-resistant breast cancer patients.
AB - Although adjuvant tamoxifen therapy is beneficial to estrogen receptor-positive (ER+) breast cancer patients, a significant number of patients still develop metastasis or undergo recurrence. Therefore, identifying novel diagnostic and prognostic biomarkers for these patients is urgently needed. Predictive markers and therapeutic strategies for tamoxifen-resistant ER+ breast cancer are not clear, and micro (mi)RNAs have recently become a focal research point in cancer studies owing to their regulation of gene expressions, metabolism, and many other physiological processes. Therefore, systematic investigation is required to understand the modulation of gene expression in tamoxifen-resistant patients. High-throughput technology uses a holistic approach to observe differences among expression profiles of thousands of genes, which provides a comprehensive level to extensively investigate functional genomics and biological processes. Through a bioinformatics analysis, we revealed that glutamine synthetase/glutamate-ammonia ligase (GLUL) might play essential roles in the recurrence of tamoxifen-resistant ER+ patients. GLUL increases intracellular glutamine usage via glutaminolysis, and further active metabolism-related downstream molecules in cancer cell. However, how GLUL regulates tumor immunology for tamoxifen-resistant ER+ breast cancer remains unexplored. Analysis of MetaCore pathway database demonstrated that GLUL is involved in the cell cycle, immune response, interleukin (IL)-4-induced regulators of cell growth, differentiation, and metabolism-related pathways. Experimental data also confirmed that the knockdown of GLUL in breast cancer cell lines decreased cell proliferation and influenced expressions of downstream molecules. Through a Connectivity Map (CMap) analysis, we revealed that certain drugs/molecules, including omeprazole, methacholine chloride, ioversol, fulvestrant, difenidol, cycloserine, and MK-801, may serve as potential treatments for tamoxifen-resistant breast cancer patients. These drugs may be tested in combination with current therapies in tamoxifen-resistant breast cancer patients. Collectively, our study demonstrated the crucial roles of GLUL, which provide new targets for the treatment of tamoxifen-resistant breast cancer patients.
KW - bioinformatics
KW - breast cancer
KW - glutamine synthetase (GLUL)
KW - immune microenvironment
KW - tamoxifen
UR - http://www.scopus.com/inward/record.url?scp=85143766315&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85143766315&partnerID=8YFLogxK
U2 - 10.7150/ijms.75625
DO - 10.7150/ijms.75625
M3 - Article
C2 - 36619229
AN - SCOPUS:85143766315
SN - 1449-1907
VL - 20
SP - 35
EP - 49
JO - International Journal of Medical Sciences
JF - International Journal of Medical Sciences
IS - 1
ER -
