NRF2 regulates serine biosynthesis in non–small cell lung cancer

DeNicola, Gina M.; Chen, Pei Hsuan; Mullarky, Edouard; Sudderth, Jessica; Hu, Zeping; Wu, David; Tang, Jing; Xie, Yang; Asara, John M.; Huffman, Kenneth E.; Wistuba, Ignacio I.; Minna, John D.; DeBerardinis, Ralph J.; Cantley, Lewis C.

doi:10.1038/ng.3421

Cited by 578 publications

(627 citation statements)

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“…[ 13 C 6 ]Glc is a commonly used tracer for measuring glycolysis as it is relatively inexpensive and will label all glycolytic carbons derived from Glc, and it enables tracing of glycolysis-derived precursors in other pathways. For example, phosphoglycerate, which is a substrate for purine synthesis via the Ser-Gly one-carbon pathway (18). However, due to ambiguities in resolving [ 13 C 3 ]lactate production from [ 13 C 6 ]Glc because of pathways other than glycolysis, Glc tracers labeled at 13 C 1 -2 or 13 C 1 -3 can provide better estimation of glycolytic flux (19).…”

Section: Glycolysismentioning

confidence: 99%

“…One of the earliest insights into cancer metabolism came when Otto Warburg noted increased uptake and fermentation of glucose (Glc) 3 to lactate in tumors relative to surrounding tissue, even in the presence of ample oxygen (2). Clinical cancer diagnosis exploits this "Warburg effect" by measuring uptake of the Glc analogue 18 F-deoxyglucose using positron emission tomography (PET), as the metabolic demands of differentiated, non-proliferating tissues generally require far less Glc than tumors (3).…”

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confidence: 99%

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Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

Bruntz

Lane

Higashi

et al. 2017

Journal of Biological Chemistry

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Metabolic reprogramming is a hallmark of cancer. The changes in metabolism are adaptive to permit proliferation, survival, and eventually metastasis in a harsh environment. Stable isotope-resolved metabolomics (SIRM) is an approach that uses advanced approaches of NMR and mass spectrometry to analyze the fate of individual atoms from stable isotope-enriched precursors to products to deduce metabolic pathways and networks. The approach can be applied to a wide range of biological systems, including human subjects. This review focuses on the applications of SIRM to cancer metabolism and its use in understanding drug actions.Metabolism is the collection of predominantly enzyme-catalyzed biochemical transformations that meet the growth and survival demands of an organism. For nearly a century, scientists have documented profound metabolic changes that occur in tumors (1, 2). One of the earliest insights into cancer metabolism came when Otto Warburg noted increased uptake and fermentation of glucose (Glc) 3 to lactate in tumors relative to surrounding tissue, even in the presence of ample oxygen (2). Clinical cancer diagnosis exploits this "Warburg effect" by measuring uptake of the Glc analogue 18 F-deoxyglucose using positron emission tomography (PET), as the metabolic demands of differentiated, non-proliferating tissues generally require far less Glc than tumors (3).Oncoproteins and tumor suppressors are well-established regulators of metabolism, and mutations or dysregulated expression can lead to the altered metabolic phenotypes observed in many cancers (4, 5). Inactivating mutations in enzymes such as fumarate hydratase (FH) or succinate dehydrogenase (SDH) induce pathophysiological accumulation of substrates that inhibit other critical enzyme functions, whereas less common gain-of-function mutations such as in isocitrate dehydrogenases (IDH) produce metabolites that directly deregulate cellular processes (6). Additionally, cancer cells frequently express fetal isoforms of metabolic enzymes that are subject to different regulatory mechanisms to provide growth advantages (7). Gaining a systematic understanding of the metabolic changes that occur during carcinogenesis can thus be exploited for therapeutic and diagnostic purposes.Stable isotope-resolved metabolomics (SIRM) is a powerful approach developed by others and by us where isotopically enriched precursors such as [ 13 C 6 ]Glc are administered to a biological system, and the ensuing metabolic transformations are determined using appropriate analytic techniques to enable robust reconstruction of metabolic pathways (8 -11). Stable isotopes are non-radioactive and in SIRM practice are identical chemically and functionally to the most abundant isotope of that element. Incorporating stable isotopes such as 2 H, 13 C, or 15 N into biological precursors has long been used to trace their metabolism in living systems (12). SIRM is thus distinct from non-tracer-based metabolomics profiling for statistical models. Here, we review SIRM applications and demonstrate h...

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Section: Glycolysismentioning

confidence: 99%

mentioning

confidence: 99%

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

Bruntz

Lane

Higashi

et al. 2017

Journal of Biological Chemistry

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“…Multiple transcription factors also cooperate to induce an antioxidant response that promotes survival, including NRF2 and ATF4. NRF2 and ATF4 promote the expression of serine/glycine biosynthesis enzymes to increase glutathione synthesis (DeNicola et al 2015) as well as heme oxygenase 1 (Dey et al 2015), each of which reduces oxidative stress, blocks anoikis, and promotes survival during metastasis.…”

Section: Ros and Metastasismentioning

confidence: 99%

Cancer, Oxidative Stress, and Metastasis

Gill

Piskounova

Morrison

2016

Cold Spring Harb Symp Quant Biol

207

141

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Reactive oxygen species (ROS) are highly reactive molecules that arise from a number of cellular sources, including oxidative metabolism in mitochondria. At low levels they can be advantageous to cells, activating signaling pathways that promote proliferation or survival. At higher levels, ROS can damage or kill cells by oxidizing proteins, lipids, and nucleic acids. It was hypothesized that antioxidants might benefit high-risk patients by reducing the rate of ROS-induced mutations and delaying cancer initiation. However, dietary supplementation with antioxidants has generally proven ineffective or detrimental in clinical trials. High ROS levels limit cancer cell survival during certain windows of cancer initiation and progression. During these periods, dietary supplementation with antioxidants may promote cancer cell survival and cancer progression. This raises the possibility that rather than treating cancer patients with antioxidants, they should be treated with pro-oxidants that exacerbate oxidative stress or block metabolic adaptations that confer oxidative stress resistance.

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“…Genetic inhibition of Nrf2 decreased the mRNA expression of the serine biosynthesis pathway's enzymes, showing the role of Nrf2 as a regulator of this pathway, via activating transcription factor 4 (ATF4), a direct transcriptional target of Nrf2 [138] and/or heterodimerization partner of Nrf2 [139]. This pathway regulates glutathione formation through the cysteine and glycine labeled from glucose [140], demonstrating the role of Nrf2 on the interplay between glutamine consumption and glucose utilization through the serine biosynthetic pathway.…”

Section: Cellular Redox Balance and Stress Resistancementioning

confidence: 99%

Glutamine at focus: versatile roles in cancer

2015

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Your article is protected by copyright and all rights are held exclusively by International Society of Oncology and BioMarkers (ISOBM).Abstract During the past decade, a heightened understanding of metabolic pathways in cancer has significantly increased. It is recognized that many tumor cells are genetically programmed and have involved an abnormal metabolic state. Interestingly, this increased metabolic autonomy generates dependence on various nutrients such as glucose and glutamine. Both of these components participate in various facets of metabolic activity that allow for energy production, synthesis of biomass, antioxidant defense, and the regulation of cell signaling. Here, we outline the emerging data on glutamine metabolism and address the molecular mechanisms underlying glutamine-induced cell survival. We also discuss novel therapeutic strategies to exploit glutamine addiction of certain cancer cell lines.

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NRF2 regulates serine biosynthesis in non–small cell lung cancer

Cited by 578 publications

References 31 publications

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

Cancer, Oxidative Stress, and Metastasis

Glutamine at focus: versatile roles in cancer

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