Pyruvate carboxylase is critical for non–small-cell lung cancer proliferation

Sellers, Katherine; Fox, Matthew P.; Bousamra, Michael; Slone, Stephen P.; Higashi, Richard M.; Miller, Donald M.; Wang, Yali; Yan, Jun; Yuneva, Mariia; Deshpande, Rahul; Lane, Andrew N.; Fan, Teresa W.‐M.

doi:10.1172/jci72873

Cited by 439 publications

(528 citation statements)

References 44 publications

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“…Similarly, 13 C labeling was higher in mouse orthotopic human GBM tumors following injection of [ 13 C]Glc compared with [ 13 C]Gln, suggesting that these tumors use less Gln in vivo (53). Tumors resected following [ 13 C 6 ]Glc infusion produce [ 13 C 3 ]citrate, -malate, and -aspartate, which is consistent with active PC, suggesting that both routes of anaplerosis are utilized by tumors depending on nutrient availability (30,37,46). These studies also suggest that metabolic alterations occur during adaptation to cell culture and/or that the tumor microenvironment substantially influences tumor metabolism (53).…”

Section: Sirm Profiling Of Cancer Systems Can Reveal Novel Metabolic mentioning

confidence: 70%

“…For example, recent studies have demonstrated the importance of the microenvironment for tumor metabolism either through immune modulation (22) or through direct regulation by stromal cells (93). Our group has demonstrated that ex vivo cultured tumor slices from primary tumors are viable metabolically and immunologically with the maintenance of the 3D tumor architecture and microenvironment (22,30,39,94). These ex vivo slices provide the unique opportunity to study the effects of environmental variants or drug treatment on metabolic networks directly in human tumors without systemic complications.…”

Section: Concluding Remarks/future Directionsmentioning

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: Sirm Profiling Of Cancer Systems Can Reveal Novel Metabolic mentioning

confidence: 70%

Section: Concluding Remarks/future Directionsmentioning

confidence: 99%

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

Bruntz

Lane

Higashi

et al. 2017

Journal of Biological Chemistry

Self Cite

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“…The importance of glutamine as a nitrogen reservoir is underscored by the fact that glutaminedeprived cancer cells undergo cell cycle arrest that cannot be rescued by TCA-cycle intermediates such as oxaloacetate but can be rescued by exogenous nucleotides 118,119 . In fact, synthesis of nucleotides from exogenous glutamine has been observed in human primary lung cancer samples cultured ex vivo 120 .…”

Section: Nucleotide Biosynthesismentioning

confidence: 99%

“…Cancers that depend on GLS2 61, 64 , which is not sensitive to BPTES or CB-839, would be unlikely to respond to therapy 174 . The expression of pyruvate carboxylase, which can provide carbon to the TCA cycle through its conversion of pyruvate to oxaloacetate, represents a potential mechanism for glutaminase independence 120,175 . Glutamine synthetase (GLUL) expression may also predict glutamine independence and promote BPTES resistance 171,[176][177][178] .…”

Section: Therapymentioning

confidence: 99%

“…As an illustrative example of the metabolic complexity of tumors, lung cancer cell lines are often glutamine dependent in vitro, but a recent study of K-RAS driven mouse lung tumors demonstrated that glucose but not glutamine was preferentially used to supply carbon to the TCA cycle, through the action of pyruvate carboxylase 190 . Furthermore, two recent metabolomics and metabolic flux studies of primary human lung cancer showed little change in glutamine entry into the TCA cycle, and instead suggested that human lung cancer can synthesize glutamine from the TCA cycle 120,191 . Human and mouse gliomas exhibit high rates of glucose catabolism and accumulate but do not avidly metabolize glutamine 168 , and do not depend on circulating glutamine to maintain cancer growth, but instead utilize glucose to synthesize glutamine through glutamine synthetase to support nucleotide biosynthesis [169][170][171] .…”

Section: Glutamine Usage: Plastic Versus Patientmentioning

confidence: 99%

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Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Altman¹,

Stine²,

Dang³

2016

Nat Rev Cancer

236

136

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The resurgence of research in cancer metabolism has recently broadened interests beyond glucose and the Warburg Effect to other nutrients including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.

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Metabolomic, transcriptomic and genetic integrative analysis reveals important roles of adenosine diphosphate in haemostasis and platelet activation in non‐small‐cell lung cancer

et al. 2019

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Lung cancer is the leading cause of cancer-related deaths in the world. The most prevalent subtype, accounting for 85% of cases, is non-small-cell lung cancer (NSCLC). Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the most common subtypes. Despite recent advances in treatment, the low 5-year survival rate of NSCLC patients (approximately 13%) reflects the lack of early diagnostic biomarkers and incomplete understanding of the underlying disease mechanisms. We hypothesized that integration of metabolomic, transcriptomic and genetic profiles of tumours and matched normal tissues could help to identify important factors and potential therapeutic targets that contribute to tumorigenesis. We integrated omics profiles in tumours and matched adjacent normal tissues of patients with LUSC (N = 20) and LUAD (N = 17) using multiple system biology approaches. We confirmed the presence of previously described metabolic pathways in NSCLC, particularly those mediating the Warburg effect. In addition, through our combined omics analyses we found that metabolites and genes that contribute to haemostasis, angiogenesis, platelet activation and cell proliferation were predominant in both subtypes of NSCLC. The important roles of adenosine diphosphate in promoting cancer metastasis through platelet activation and angiogenesis suggest this metabolite could be a potential therapeutic target.Abbreviations ADP, adenosine diphosphate; HMDB, Human Metabolome Database; LC/MS, liquid chromatography/mass spectrometry; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; NSCLC, non-small-cell lung cancer; WGCNA, weighted gene co-expression network analysis.

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Pyruvate carboxylase is critical for non–small-cell lung cancer proliferation

Cited by 439 publications

References 44 publications

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

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

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Metabolomic, transcriptomic and genetic integrative analysis reveals important roles of adenosine diphosphate in haemostasis and platelet activation in non‐small‐cell lung cancer

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