Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer

Sivanand, Sharanya; Heiden, Matthew G. Vander

doi:10.1016/j.ccell.2019.12.011

Cited by 310 publications

(225 citation statements)

References 96 publications

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“…BCAA catabolism is mediated by the cytosolic branched-chain amino acid transaminase 1 (BCAT1) and mitochondrial branched-chain amino acid transaminase 2 (BCAT2) which transfer the amino groups from BCAAs to α-KG to produce branched-chain α-keto acids (BCKAs) and glutamate. BCAA breakdown can not only provide carbon for synthesis of metabolites to fuel TCA cycle which can contribute to energy production but also supply nitrogen for de novo nucleotide and non-essential amino acid biosynthesis in cancer (21). It has been shown that plasma BCAAs levels are elevated in early-stage pancreatic cancers driven by mutant KRAS (22).…”

Section: Krasmentioning

confidence: 99%

Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies

Yang

Ren

et al. 2020

Front. Oncol.

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies with an extremely poor prognosis. Energy metabolism reprogramming, an emerging hallmark of cancer, has been implicated in the tumorigenesis and development of pancreatic cancer. In addition to well-elaborated enhanced glycolysis, investigating the role of reprogramming of amino acid metabolism has sparked great interests in recent years. The rewiring amino acid metabolism orchestrated by genetic alterations contributes to pancreatic cancer malignant characteristics including cell proliferation, invasion, metastasis, angiogenesis and redox balance. In the unique hypoperfused and nutrient-deficient tumor microenvironment (TME), the interactions between cancer cells and stromal components and salvaging processes including autophagy and macropinocytosis play critical roles in fulfilling the metabolic requirements and supporting growth of PDAC. In this review, we elucidate the recent advances in the amino acid metabolism reprogramming in pancreatic cancer and the mechanisms of amino acid metabolism regulating PDAC progression, which will provide opportunities to develop promising therapeutic strategies.

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Section: Krasmentioning

confidence: 99%

Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies

Yang

Ren

et al. 2020

Front. Oncol.

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“…The downstream mechanism of how BCAAs are affecting cell survival in ATM inhibited cells remains unknown. The irreversible step of BCAA metabolism via the branched chain alpha-keto acid dehydrogenase (BCKDH) complex generates mitochondrial NADH in addition to providing acetyl-and succinyl-CoA to the TCA cycle, and BCAAs have been shown to inhibit ROS (Sivanand and Vander Heiden, 2020). Since ATM inhibition increases ROS (Valentin-Vega et al, 2012), which in turn can promote AMPK activation (Rabinovitch et al, 2017), it is possible that BCAAs are consumed to promote redox homeostasis.…”

Section: Macropinocytosis Induced By Atm Inhibition Increases Bcaa Upmentioning

confidence: 99%

ATM inhibition drives metabolic adaptation via induction of macropinocytosis

Chen

Buj

Dahl

et al. 2020

Preprint

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Macropinocytosis is a nonspecific endocytic process that enhances cancer cell survival under nutrient-poor conditions. Ataxia-Telangiectasia mutated (ATM) is a tumor suppressor that plays a role in cellular metabolic reprogramming. We report that suppression of ATM increases macropinocytosis in an AMPK-dependent manner to promote cancer cell survival in nutrient-poor conditions. Combined inhibition of ATM and macropinocytosis suppressed proliferation and induced cell death both in vitro and in vivo.Metabolite analysis of the ascites and interstitial fluid from tumors indicated decreased branched chain amino acids (BCAAs) in the microenvironment of ATM-inhibited tumors. Supplementation of ATM inhibitor-treated cells with BCAAs abrogated AMPKphosphorylation and macropinocytosis and rescued the cell death that occurs due to combined inhibition of ATM and macropinocytosis. These data reveal a novel molecular basis of ATM-mediated tumor suppression whereby loss of ATM promotes protumorigenic uptake of nutrients to promote cancer cell survival and reveal a metabolic vulnerability of ATM-inhibited cells.

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“…RT cells show an active oxidative metabolism RT4 cells show increased consumption of arginine, glutamine, BCAAs and serine, along with increased excretion of formate with respect to 5637 cells (Figure 3). All these compounds are related to metabolic pathways that occur inside the mitochondria, require an active oxidative metabolism, and were already found altered in different tumors and cancer cell lines [9][10][11]. RT4 cells show also a higher serine consumption than the other two cell lines, along with a higher excretion of a product of its catabolism, formate, a further con rmation of an active mitochondrial activity and active oxidative phosphorylation metabolism (OxPhos) [12].…”

Section: Glycolysis Is the Most Active Metabolic Pathway In 5637 Cellsmentioning

confidence: 98%

The Interplay Between Oxidative Phosphorylation and Glycolysis as a Potential Marker of Bladder Cancer Progression in Vitro and in Vivo

Petrella

Ciufolini

Burgio

et al. 2020

Preprint

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BackgroundUrothelial bladder cancer (UBC) is the most common tumor of the urinary system, the ninth most common cancer worldwide and the one with the most expensive treatment from diagnosis to death. One of the biggest problems related to this disease is the lack of sufficiently accurate markers that can anticipate the progression of the cancer from a low-grade non-muscle invasive to a high-grade muscle invasive UBC. Genomics and transcriptomics have recently added a number of molecular markers to traditional observations based on pathological parameters, which have greatly improved the prediction of risk of recurrence and progression. The inclusion of information from other omics sciences, such as metabolomics, could significantly improve this scenario.MethodsIn this study, we present the metabolic characterization using 1H-NMR of three UBC cell lines representing tumors with low-risk of progression, RT4, high-risk, 5637, and a cell line that shares characteristics with both, RT112. The metabolic profiles were classified by multivariate analysis. To validate the in vitro results, concentrations of two metabolites were measured in vivo in the urine of 91 patients with non-invasive and invasive tumors.ResultsRT4 cells mainly use oxidative phosphorylation to produce ATP and biomass, 5637 cells depend mainly on glycolysis, while RT112 cells show a mixed state with both metabolisms partially activated. The lactate/alanine ratio proved to be the most sensitive marker to the different type of metabolism active in the cells in vitro. By measuring its value in vivo in urine, we have found a two-fold increase among patients with high-grade tumors compared to low-grade ones.ConclusionsOur results reveal for the first time the relative importance of glycolysis and oxidative phosphorylation in the growth and maintenance of different UBC cell lines, and the relationship with their genomic signatures. They suggest that oxidative and non-oxidative metabolic states are primarily related to cell lines with low and high risk of progression, respectively. From this observation and our preliminary in vivo results, it appears that the lactate/alanine ratio in patients' urine is a good candidate to become a new marker to predict the conversion of low-grade tumors into more malignant forms.

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Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer

Cited by 310 publications

References 96 publications

Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies

Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies

ATM inhibition drives metabolic adaptation via induction of macropinocytosis

The Interplay Between Oxidative Phosphorylation and Glycolysis as a Potential Marker of Bladder Cancer Progression in Vitro and in Vivo

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