Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models

Svensson, Robert; Parker, Seth J.; Eichner, Lillian J.; Kolar, Matthew J.; Wallace, Martina; Brun, Sonja N.; Lombardo, Portia S.; Nostrand, Jeanine L. Van; Hutchins, Amanda; Vera, Lilliana; Gerken, Laurie; Greenwood, Jeremy R.; Bhat, Sathesh; Harriman, Geraldine; Westlin, William; Harwood, H. James; Saghatelian, Alan; Kapeller, Rosana; Metallo, Christian M.; Shaw, Reuben J.

doi:10.1038/nm.4181

Cited by 392 publications

(361 citation statements)

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“…Among them, several molecules against ACC have been developed. 21 In a recent study, it was shown that ND-646, an allosteric ACC1/2 inhibitor, suppresses tumor growth in both xenograft and genetic engineered mouse models of non-small cell lung cancer, either alone or in combination with standard-of-care drug carboplatin, 53 supporting the further testing of ACC inhibitors for cancer treatment.…”

Section: Fasn Is Required For Akt and Akt/c-met Driven Hepatocarcinogmentioning

confidence: 98%

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

et al. 2017

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Hepatocellular carcinoma (HCC), the most frequent primary tumor of the liver, is an aggressive cancer type with limited treatment options. Cumulating evidence underlines a crucial role of aberrant lipid biosynthesis (a process known as de novo lipogenesis) along carcinogenesis. Previous studies showed that suppression of fatty acid synthase (FASN), the major enzyme responsible for de novo lipogenesis, is highly detrimental for the in vitro growth of HCC cell lines. To assess whether de novo lipogenesis is required for liver carcinogenesis, we have generated various mouse models of liver cancer by stably overexpressing candidate oncogenes in the mouse liver via hydrodynamic gene delivery. We found that overexpression of FASN in the mouse liver is unable to malignantly transform hepatocytes. However, genetic deletion of FASN totally suppresses hepatocarcinogenesis driven by AKT and AKT/c-Met protooncogenes in mice. On the other hand, liver tumor development is completely unaffected by FASN depletion in mice coexpressing b-catenin and c-Met. Our data indicate that tumors might be either addicted to or independent from de novo lipogenesis for their growth depending on the oncogenes involved. Additional investigation is required to unravel the molecular mechanisms whereby some oncogenes render cancer cells resistant to inhibition of de novo lipogenesis.

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Section: Fasn Is Required For Akt and Akt/c-met Driven Hepatocarcinogmentioning

confidence: 98%

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

et al. 2017

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“…Anti-cancer target discovery is one of the most promising translational applications for SIRM, and inhibitors of several targets have been developed and are showing promise in preclinical models (81). These inhibitors can also potentiate the efficacy of conventional chemotherapeutics (82).…”

Section: Applications Of Sirm In Drug Developmentmentioning

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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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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“…These data are in agreement with previous studies indicating that hepatocytes (Dzamko et al ., 2010) and macrophages (Fullerton et al ., 2015) from AMPK β1‐deficient mice have increased lipid synthesis and that activation of AMPK using A769662 or metformin lowers lipogenesis through an AMPK β1‐dependent pathway requiring the phosphorylation of ACC (Fullerton et al ., 2013). These data are also consistent with recent studies indicating that inhibiting lipogenesis, by mimicking AMPK phosphorylation of ACC using small molecules (Svensson et al ., 2016) or through chemical inhibition of fatty acid synthase (Menendez and Lupu, 2007; Orita et al ., 2008), is effective for limiting cellular proliferation. However, it is possible that the inhibition of proliferation is not directly related to the blunting of lipid synthesis but rather a buildup of malonyl‐CoA or some other metabolite.…”

Section: Discussionmentioning

confidence: 99%

“…Increases in fatty acid synthesis are required to sustain rapid proliferation in many types of cancer [for review, see (Hanahan and Weinberg, 2011; Hirschey et al ., 2015)] including prostate and non‐small‐cell lung cancer (NSCLC) (Shah et al ., 2016; Svensson et al ., 2016; Villani et al ., 2016). Rates of fatty acid synthesis are governed by the expression of ATP‐citrate lyase (ACLY), acetyl‐CoA carboxylase (ACC), and fatty acid synthase (FAS) (Hanahan and Weinberg, 2011; Hirschey et al ., 2015; Shah et al ., 2016; Svensson et al ., 2016; Villani et al ., 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Rates of fatty acid synthesis are governed by the expression of ATP‐citrate lyase (ACLY), acetyl‐CoA carboxylase (ACC), and fatty acid synthase (FAS) (Hanahan and Weinberg, 2011; Hirschey et al ., 2015; Shah et al ., 2016; Svensson et al ., 2016; Villani et al ., 2016). While AMPK may regulate multiple branches of the lipogenic pathway, direct phosphorylation of ACC has been shown to result in the inhibition of ACC activity, thereby preventing the conversion of acetyl‐CoA to malonyl‐CoA and blocking the entire lipogenic program (Fullerton et al ., 2013; Munday et al ., 1988).…”

Section: Introductionmentioning

confidence: 99%

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AMPK β1 reduces tumor progression and improves survival in p53 null mice

Houde

Donzelli²,

Sacconi³

et al. 2017

Molecular Oncology

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The AMP‐activated protein kinase (AMPK) is a heterotrimeric protein complex that is an important sensor of cellular energy status. Reduced expression of the AMPK β1 isoform has been linked to reduced survival in different cancers, but whether this accelerates tumor progression and the potential mechanism mediating these effects are not known. Furthermore, it is unknown whether AMPK β1 is implicated in tumorigenesis, and if so, what tissues may be most sensitive. In the current study, we find that in the absence of the tumor suppressor p53, germline genetic deletion of AMPK β1 accelerates the appearance of a T‐cell lymphoma that reduces lifespan compared to p53 deficiency alone. This increased tumorigenesis is linked to increases in interleukin‐1β (IL1β), reductions in acetyl‐CoA carboxylase (ACC) phosphorylation, and elevated lipogenesis. Collectively, these data indicate that reductions in the AMPK β1 subunit accelerate the development of T‐cell lymphoma, suggesting that therapies targeting this AMPK subunit or inhibiting lipogenesis may be effective for limiting the proliferation of p53‐mutant tumors.

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Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models

Cited by 392 publications

References 42 publications

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

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

AMPK β1 reduces tumor progression and improves survival in p53 null mice

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