Systematic analyses of glutamine and glutamate metabolisms across different cancer types

Abstract

BackgroundGlutamine and glutamate are known to play important roles in cancer biology. However, no detailed information is available in terms of their levels of involvement in various biological processes across different cancer types, whereas such knowledge could be critical for understanding the distinct characteristics of different cancer types. Our computational study aimed to examine the functional roles of glutamine and glutamate across different cancer types.MethodsWe conducted a comparative analysis of gene expression data of cancer tissues versus normal control tissues of 11 cancer types to understand glutamine and glutamate metabolisms in cancer. Specifically, we developed a linear regression model to assess differential contributions by glutamine and/or glutamate to each of seven biological processes in cancer versus control tissues.ResultsWhile our computational predictions were consistent with some of the previous observations, multiple novel predictions were made: (1) glutamine is generally not involved in purine synthesis in cancer except for breast cancer, and is similarly not involved in pyridine synthesis except for kidney cancer; (2) glutamine is generally not involved in ATP production in cancer; (3) glutamine’s contribution to nucleotide synthesis is minimal if any in cancer; (4) glutamine is not involved in asparagine synthesis in cancer except for bladder and lung cancers; and (5) glutamate does not contribute to serine synthesis except for bladder cancer.ConclusionsWe comprehensively predicted the roles of glutamine and glutamate metabolisms in selected metabolic pathways in cancer tissues versus control tissues, which may lead to novel approaches to therapeutic development targeted at glutamine and/or glutamate metabolism. However, our predictions need further functional validation.

1H NMR metabolomics reveals increased glutaminolysis upon overexpression of NSD3s or Pdp3 in Saccharomyces cerevisiae

“…44,45 The metabolomics profile of NSD3s + and Pdp3 + is similar; however, not identical, indicating that each protein acts by regulating a common core of metabolic pathways in addition to a handful of other proteinspecific reactions. Consistent to our findings, these metabolic alterations have been frequently found in several types of tumors, including those in which NSD3s overexpression is reported 33,38,40,41,[52][53][54][55][56][57] . This effect is a characteristic of the metabolic alterations found in tumorigenesis, in which tumor cells adapt their pathways to the production of macromolecules necessary to sustain growth and survival.…”

“…46,48,51 Our metabolomics screening revealed arginine, alanine, glutamate, and valine as molecular signatures of NSD3s overexpression in yeast. Consistent to our findings, these metabolic alterations have been frequently found in several types of tumors, including those in which NSD3s overexpression is reported 33,38,40,41,[52][53][54][55][56][57] . Thus, our results provided novel insights into the molecular mechanisms underlying NSD3s-induced carcinogenesis.…”

Bioinformatics and functional analyses of key genes and pathways in human clear cell renal cell carcinoma

“…The present study demonstrated that the most significant functions and pathways identified were associated with biological metabolism. Previous studies have indicated that molecular metabolisms served a comprehensive role in the process of tumor generation and development ( 20 , 21 ). It is known that HIF and the hypoxic response serve a key role in the pathways that are involved in tumorigenesis ( 22 ).…”

Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer

“…Cancer cells extensively reprogram their metabolic pathways to support increased biosynthetic and bioenergetic demands. One common mechanism employed by cancer cells for metabolic reprogramming is to increase uptake of nutrients critical for biosynthetic and bioenergetic processes in cancer cells, including glucose and amino acids such as glutamine [ 5 , 6 ]. Cancer cells achieve this by mainly upregulating various transporters that mediate uptake of glucose and amino acids.…”