Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Neitzel, Carina; Demuth, Philipp; Wittmann, Simon; Fahrer, Jörg

doi:10.3390/cancers12071731

Cited by 40 publications

(47 citation statements)

References 243 publications

(338 reference statements)

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“…22 The ultimate goal of a metabolic reprogramming is to increase the growth rate of cancer cells and provide substrates for their biosynthetic pathways. 23 The metabolites of the TCA cycle, such as α-ketoglutarate, succinic acid, and fumaric acid, may also be involved in conduction of carcinogenic signals. The oxidative phosphorylation process is also considered to be related to the proliferation, metastasis and drug resistance of CRC, and may be a bridge for certain carcinogenic molecules to play a carcinogenic effect.…”

Section: Discussionmentioning

confidence: 99%

Metabolic profiling analysis for clinical urine of colorectal cancer

Qiao

Zhang

et al. 2021

Asia-Pac J Clncl Oncology

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Aim:To demonstrate the little-known metabolic changes and pathways in patients with colorectal cancer (CRC). Methods:We used gas chromatography time-of-flight mass spectrometry (GC-TOF/MS) to perform metabolic profiling of urine samples from 163 consecutive patients with CRC and 111 healthy controls without history of gastrointestinal tumors. The metabolic profiles were assayed using multivariate statistical analysis and oneway analysis of variance, and further analyzed to identify potential marker metabolites related to CRC. The GC-TOF/MS-derived models showed clear discriminations in metabolic profiles between the CRC group and healthy control group. Results:We demonstrated that 15 metabolites contributed to the differences. Among them, eleven metabolites were significantly upregulated, while other four metabolites were downregulated in the urine samples of CRC patients compared with healthy controls. Pathway analysis revealed changes in energy metabolism of patients with CRC, which are reflected in the upregulation of glycolysis and amino acid metabolism and the downregulation of lipid metabolism. Our study revealed the metabolic profile of urine from CRC patients and indicated that GC-TOF/MS-based methods can distinguish CRC from healthy controls. Conclusion:GC-TOF/MS-based metabolomics has the potential to be developed into a novel, non-invasive, and painless clinical tool for CRC diagnosis, and may contribute to an improved understanding of disease mechanisms.

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Section: Discussionmentioning

confidence: 99%

Metabolic profiling analysis for clinical urine of colorectal cancer

Qiao

Zhang

et al. 2021

Asia-Pac J Clncl Oncology

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“…Colon cells have adapted to high concentrations of SCFAs and have altered their metabolism accordingly 65 . In line with this, studies show that colorectal cancers have a higher copy number of mitochondrial DNA that is accompanied by an increased oxidative phosphorylation 66‐68 . It is thus possible that colon cancer cells are less sensitive to propionate‐mediated mitochondrial changes compared with Jurkat cells.…”

Section: Discussionmentioning

confidence: 88%

“…65 In line with this, studies show that colorectal cancers have a higher copy number of mitochondrial DNA that is accompanied by an increased oxidative phosphorylation. [66][67][68] It is thus possible that colon cancer cells are less sensitive to propionate-mediated mitochondrial changes compared with Jurkat cells. Colon cancer cells; nonetheless, upregulate NKG2D ligand surface expression in response to propionate, suggesting that parts of the MICA/B regulatory mechanism in Jurkat cells and colon cancer cells are overlapping and likely depend on increased short-chain acyl-CoA-mediated acylation.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of short‐chain fatty acid propionate induces surface expression of NKG2D ligands on cancer cells

et al. 2020

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SCFAs are primarily produced in the colon by bacterial fermentation of nondigestible carbohydrates. Besides providing energy, SCFAs can suppress development of colon cancer. The mechanism, however, remains elusive. Here, we demonstrate that the SCFA propionate upregulates surface expression of the immune stimulatory NKG2D ligands, MICA/B by imposing metabolic changes in dividing cells. Propionate-mediated MICA/B expression did not rely on GPR41/GPR43 receptors but depended on functional mitochondria. By siRNA-directed knockdown, we could further link phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme in gluconeogenesis to propionate regulation of MICA/B expression. Moreover, knockdown of Rictor and specific mTOR inhibitors implicated mTORC2 activity with metabolic changes that control MICA/B expression. SCFAs are precursors to short-chain acyl-CoAs that are used for histone acylation thereby linking the metabolic state to chromatin structure and gene expression. Propionate increased the overall acetylation and propionylation and inhibition of lysine acetyltransferases (KATs) that are responsible for adding acyl-CoAs to histones reduced propionate-mediated MICA/B expression, suggesting that propionate-induced acylation increases MICA/B expression. Notably, propionate upregulated MICA/B surface expression on colon cancer cells in an acylation-dependent manner; however, the impact of mitochondrial metabolism on MICA/B expression was different in colon cancer cells compared with Jurkat cells, suggesting that continuous exposure to propionate in the colon may provide an enhanced capacity to metabolize propionate. Together, our findings support that propionate causes metabolic changes resulting in NKG2D ligand surface expression, which holds potential as an immune activating anticancer therapy.

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“…The role of p53 in the upregulation of crucial players in electron chain transport, such as SCO2 (synthesis of cytochrome c oxidase 2), was reported in CRC cells [179]. In normal conditions, p53 stimulated PDC activity as well as OXPHOs by inhibiting PDK2 is observed in vivo and in vitro, while the mutant p53 upregulated PDK2 in CRC [14,180].…”

Section: P53 Influences Crc Metabolismmentioning

confidence: 92%

Metabolic Reprogramming of Colorectal Cancer Cells and the Microenvironment: Implication for Therapy

Nenkov

Gaßler

et al. 2021

IJMS

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Colorectal carcinoma (CRC) is one of the most frequently diagnosed carcinomas and one of the leading causes of cancer-related death worldwide. Metabolic reprogramming, a hallmark of cancer, is closely related to the initiation and progression of carcinomas, including CRC. Accumulating evidence shows that activation of oncogenic pathways and loss of tumor suppressor genes regulate the metabolic reprogramming that is mainly involved in glycolysis, glutaminolysis, one-carbon metabolism and lipid metabolism. The abnormal metabolic program provides tumor cells with abundant energy, nutrients and redox requirements to support their malignant growth and metastasis, which is accompanied by impaired metabolic flexibility in the tumor microenvironment (TME) and dysbiosis of the gut microbiota. The metabolic crosstalk between the tumor cells, the components of the TME and the intestinal microbiota further facilitates CRC cell proliferation, invasion and metastasis and leads to therapy resistance. Hence, to target the dysregulated tumor metabolism, the TME and the gut microbiota, novel preventive and therapeutic applications are required. In this review, the dysregulation of metabolic programs, molecular pathways, the TME and the intestinal microbiota in CRC is addressed. Possible therapeutic strategies, including metabolic inhibition and immune therapy in CRC, as well as modulation of the aberrant intestinal microbiota, are discussed.

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Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Cited by 40 publications

References 243 publications

Metabolic profiling analysis for clinical urine of colorectal cancer

Metabolic profiling analysis for clinical urine of colorectal cancer

Metabolism of short‐chain fatty acid propionate induces surface expression of NKG2D ligands on cancer cells

Metabolic Reprogramming of Colorectal Cancer Cells and the Microenvironment: Implication for Therapy

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