{"title":"Glutamine withdrawal leads to the preferential activation of lipid metabolism in metastatic colorectal cancer","authors":"","doi":"10.1016/j.tranon.2024.102078","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><p>Glutamine is a non-essential amino acid that is critical for cell growth. However, the differential metabolism of <span>l</span>-glutamine in metastatic versus primary colorectal cancer (CRC) has not been evaluated adequately.</p></div><div><h3>Materials and methods</h3><p>Differential expression of glutamine-related genes was determined in primary versus metastatic CRC. Univariate Cox regression and hierarchical clustering were used to generate a gene signature for prognostication. Untargeted metabolomics and <sup>18</sup>O based fluxomics were used to identify differential metabolite levels and energy turnover in the paired primary (SW480) and metastatic (SW620) CRC cells. Western blot and qRT-PCR were used to validate differential gene expression. Subcellular localization of E-cadherin was determined by immunocytochemistry. Lipid droplets were visualized with Nile Red.</p></div><div><h3>Results</h3><p>The GO term “Glutamine metabolism” was significantly enriched in metastatic versus primary tumors. Supporting this, SW620 cells showed decreased membrane localization of E-cadherin and increased motility upon <span>l</span>-Glutamine withdrawal. A glutamine related signature associated with worse prognosis was identified and validated in multiple datasets. A fluxomics assay revealed a slower TCA cycle in SW480 and SW620 cells upon <span>l</span>-Glutamine withdrawal. SW620 cells, however, could maintain high ATP levels. Untargeted metabolomics indicated the preferential metabolism of fatty acids in SW620 but not SW480 cells. Lipids were mainly obtained from the environment rather than by <em>de novo</em> synthesis.</p></div><div><h3>Conclusions</h3><p>Metastatic CRC cells can display aberrant glutamine metabolism. We show for the first time that upon <span>l</span>-glutamine withdrawal, SW620 (but not SW480) cells were metabolically plastic and could metabolize lipids for survival and cellular motility.</p></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":null,"pages":null},"PeriodicalIF":5.0000,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1936523324002055/pdfft?md5=2fd3bbf6b172bb4b7bbf73f79c8dd045&pid=1-s2.0-S1936523324002055-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Translational Oncology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1936523324002055","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction
Glutamine is a non-essential amino acid that is critical for cell growth. However, the differential metabolism of l-glutamine in metastatic versus primary colorectal cancer (CRC) has not been evaluated adequately.
Materials and methods
Differential expression of glutamine-related genes was determined in primary versus metastatic CRC. Univariate Cox regression and hierarchical clustering were used to generate a gene signature for prognostication. Untargeted metabolomics and 18O based fluxomics were used to identify differential metabolite levels and energy turnover in the paired primary (SW480) and metastatic (SW620) CRC cells. Western blot and qRT-PCR were used to validate differential gene expression. Subcellular localization of E-cadherin was determined by immunocytochemistry. Lipid droplets were visualized with Nile Red.
Results
The GO term “Glutamine metabolism” was significantly enriched in metastatic versus primary tumors. Supporting this, SW620 cells showed decreased membrane localization of E-cadherin and increased motility upon l-Glutamine withdrawal. A glutamine related signature associated with worse prognosis was identified and validated in multiple datasets. A fluxomics assay revealed a slower TCA cycle in SW480 and SW620 cells upon l-Glutamine withdrawal. SW620 cells, however, could maintain high ATP levels. Untargeted metabolomics indicated the preferential metabolism of fatty acids in SW620 but not SW480 cells. Lipids were mainly obtained from the environment rather than by de novo synthesis.
Conclusions
Metastatic CRC cells can display aberrant glutamine metabolism. We show for the first time that upon l-glutamine withdrawal, SW620 (but not SW480) cells were metabolically plastic and could metabolize lipids for survival and cellular motility.
期刊介绍:
Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.