Glutamine metabolism in the proliferation of GS-expression pituitary tumor cells

Abstract

Objective: Many cancer cells cannot survive without exogenous glutamine (Gln); however, cancer cells expressing glutamine synthetase (GS) do not have this restriction. Previous metabolomics studies have indicated that glutamine metabolism is altered during pituitary tumorigenesis. However, the main role of Gln in pituitary adenoma (PA) pathophysiology remains unknown. The aim of this study was to evaluate the expression of GS and the main role of Gln in human PAs. Methods: We used cell proliferation assay and flow cytometry to assess the effect of Gln depletion on three different pituitary cell lines and human primary PA cells. We then investigated the expression level of Gln synthetase (GS) in 24 human PA samples. At last, we used LC-MS/MS to identify the differences in metabolites of PA cells after the blockage of both endogenous and exogenous Gln. Results: PA cell lines showed different sensitivities to Gln starvation, and the sensitivity is correlated with GS expression level. GS expressed in 21 out of the 24 human PA samples. Furthermore, a positive p53 and ki-67 index was correlated with a higher GS expression level (P < 0.05). Removal of both endogenous and exogenous Gln from GS-expressing PA cells resulted in blockage of nucleotide metabolism and cell cycle arrest. Conclusions: Our data indicate that GS is needed for PA cells to undergo proliferation during Gln deprivation, and most human PA cells express GS and might have a negative response to exogenous Gln depletion. Moreover, Gln is mainly responsible for nucleotide metabolism in the proliferation of GS-expressing pituitary tumor cells.

Metabolomics in acromegaly: a systematic review

“…19,20 A study performed on animal cell cultures was removed. 21 A study that investigated PAs without specifying which of those had GH hypersecretion was excluded. 22 Three studies that evaluated duplicate groups of patients were removed.…”

Co-inhibition of glutaminolysis and one-carbon metabolism promotes ROS accumulation leading to enhancement of chemotherapeutic efficacy in anaplastic thyroid cancer

“…Glutamate is also involved in glutathione (GSH) synthesis, which is a predominant antioxidant enzyme that protects cancer cells from various oxidative stresses such as chemotherapy and radiation [ 12 – 15 ]. Based on the essential roles of glutamine in cancer cell homeostasis, it has been reported that many cancer cells such as lung adenocarcinoma; acute myeloid leukemia; breast; liver; and brain cancer are vulnerable to glutamine deprivation stress, suggesting the crucial role of glutamine in modulating cancer cell survival [ 16 – 19 ].…”

Drp1 Regulated Mitochondrial Hypofission Promotes the Invasion and Proliferation of Growth Hormone-Secreting Pituitary Adenomas via Activating STAT3

“…Transcriptiomics data ( 6 ) and metabolomics investigations ( 7 ) supported the potential oncogenetic roles of metabolic dysregulation in PAs. Our group has reported that dysregulated glucose metabolism ( 8 ), cholesterol metabolism ( 9 ) and glutamine metabolism ( 10 ) might play important roles in the tumorigenesis of PAs. For example, we have reported that lactate dehydrogenase A (LDHA) enhances the glycolysis in pituitary GH3 cells, and then promotes the invasion and proliferation of GH3 cells ( 8 ).…”