Glutamine Sensitivity Analysis Identifies the xCT Antiporter as a Common Triple-Negative Breast Tumor Therapeutic Target

Timmerman, Luika; Holton, Thomas; Yuneva, Mariia; Louie, Raymond J.; Padró, Mercè; Daemen, Anneleen; Hu, Min; Chan, Denise A.; Ethier, Stephen P.; Veer, Laura J. van ’t; Polyák, Kornélia; McCormick, Frank; Gray, Joe W.

doi:10.1016/j.ccr.2013.08.020

Cited by 465 publications

(500 citation statements)

References 56 publications

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“…We recently demonstrated that paclitaxel treatment increases the percentage of BCSCs in a HIF-dependent manner (10). xCT and GCLM expression in breast cancer cell lines is correlated with expression of CD44, an important BCSC marker (20,24). To test the role of the glutathione synthesis pathway in paclitaxel-induced BCSC enrichment, MDA-MB-231 cells were sorted into an ALDH + population, which is highly enriched for BCSCs, and an ALDH − population, which is depleted of BCSCs (11).…”

Section: Resultsmentioning

confidence: 99%

“…Glycine is added to γ-glutamylcysteine by the enzyme glutathione synthetase (GSS) to form glutathione. The glutathione synthesis pathway has been shown to promote cancer initiation and progression, and targeting this pathway by inhibiting xCT or GCL has shown some promise in inhibiting tumor growth in combination with chemotherapy in mouse models of breast cancer (20,21), although the underlying molecular mechanisms have not been fully delineated. Because chemotherapy induces oxidative stress, it has been assumed that the glutathione synthesis pathway promotes chemotherapy resistance through its antioxidant effects (17).…”

Section: Significancementioning

confidence: 99%

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Chemotherapy triggers HIF-1–dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype

Samanta

Xiang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

213

205

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Triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancer but is responsible for a disproportionate share of morbidity and mortality because of its aggressive characteristics and lack of targeted therapies. Chemotherapy induces enrichment of breast cancer stem cells (BCSCs), which are responsible for tumor recurrence and metastasis. Here, we demonstrate that chemotherapy induces the expression of the cystine transporter xCT and the regulatory subunit of glutamate-cysteine ligase (GCLM) in a hypoxia-inducible factor (HIF)-1-dependent manner, leading to increased intracellular glutathione levels, which inhibit mitogenactivated protein kinase kinase (MEK) activity through copper chelation. Loss of MEK-ERK signaling causes FoxO3 nuclear translocation and transcriptional activation of the gene encoding the pluripotency factor Nanog, which is required for enrichment of BCSCs. Inhibition of xCT, GCLM, FoxO3, or Nanog blocks chemotherapy-induced enrichment of BCSCs and impairs tumor initiation. These results suggest that, in combination with chemotherapy, targeting BCSCs by inhibiting HIF-1-regulated glutathione synthesis may improve outcome in TNBC.hypoxia-inducible factor | paclitaxel | pluripotency factors | chemotherapy resistance | tumor-initiating cells

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Section: Resultsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Chemotherapy triggers HIF-1–dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype

Samanta

Xiang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

213

205

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“…We analyzed the effect of hypoxia (1% O 2 for 24 h) on the production of MVs by three human breast cancer cell lines: MCF-7 expresses the estrogen and progesterone receptors, but not HER2, and is classified as luminal subtype based on its gene expression pattern, whereas MDA-MB-231 and MDA-MB-435 cells (hereafter designated MDA-231 and MDA-435) do not express estrogen or progesterone receptors or HER2 (i.e., triple negative) and are classified as basallike/claudin-low subtype by gene expression criteria (43,44 (29)(30)(31).…”

Section: Resultsmentioning

confidence: 99%

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

Wang

Gilkes²,

Takano³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

386

370

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Extracellular vesicles such as exosomes and microvesicles (MVs) are shed by cancer cells, are detected in the plasma of cancer patients, and promote cancer progression, but the molecular mechanisms regulating their production are not well understood. Intratumoral hypoxia is common in advanced breast cancers and is associated with an increased risk of metastasis and patient mortality that is mediated in part by the activation of hypoxiainducible factors (HIFs). In this paper, we report that exposure of human breast cancer cells to hypoxia augments MV shedding that is mediated by the HIF-dependent expression of the small GTPase RAB22A, which colocalizes with budding MVs at the cell surface. Incubation of naïve breast cancer cells with MVs shed by hypoxic breast cancer cells promotes focal adhesion formation, invasion, and metastasis. In breast cancer patients, RAB22A mRNA overexpression in the primary tumor is associated with decreased overall and metastasis-free survival and, in an orthotopic mouse model, RAB22A knockdown impairs breast cancer metastasis.orthotopic transplantation | triple negative breast cancer | oxygen | tumor microenvironment | mammary fat pad implantation

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“…18 More recently, therapeutic approaches targeting amino acid transport were suggested including for example inhibition of the glutamine transporter SLC1A5 15 and inhibition of the glutamate-cystine antiporter xCT. 19 Much of the renewed interest in therapeutically targeting of glutamine metabolism is related to the first step of glutamine utilization, the conversion of glutamine to glutamate by the enzyme glutaminase. Humans express two genes with glutaminase activity: GLS and GLS2.…”

mentioning

confidence: 99%

Glutamate enrichment as new diagnostic opportunity in breast cancer

Budczies

Pfitzner

Győrffy

et al. 2014

Intl Journal of Cancer

108

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Exogenous glutamine is an important source of energy and molecular building blocks for many tumors. There is a renewed interest in therapeutically targeting glutamine metabolism due to the recent discovery of two novel glutaminase inhibitors. To quantify the dysregulation of the glutamate-glutamine equilibrium in breast cancer, metabolomics analysis of 270 clinical breast cancer samples and 97 normal breast samples was carried out using gas chromatography combined with time-of-flight mass spectrometry. Positive correlation between glutamate and glutamine in normal breast tissues switched to negative correlation between glutamate and glutamine in breast cancer tissues. Compared with the ratio of glutamate to glutamine in normal tissues, we found 56% of the ER1 tumor tissues and 88% of the ER2 tumor tissues glutamate-enriched. The glutamateto-glutamine ratio (GGR) significantly correlated with ER status (p 5 8.0E-09) and with tumor grade (p 5 3.3E-05). Higher levels of GGR were associated with prolonged overall survival in univariate analysis (HR 5 0.77, p 5 0.027) and in multivariate analysis (HR 5 0.73, p 5 0.038). GGR levels were reflected in an unsupervised clustering of metabolomics profiles. In a supervised analysis of metabolomics data and of genome-wide expression data, replacement of GGR by metabolite surrogate markers was feasible, while replacement of GGR by RNA markers had a limited accuracy. Functional analysis of the gene expression data showed negative correlation between glutamate enrichment and activation of peroxisome proliferator-activated receptor (PPAR) pathway. Our findings may have important implications for patient stratification related to utilization of glutaminase inhibitors.Altered energy metabolism is acknowledged as one of the emerging hallmarks of cancer. 1 Recently, there is a renewed interest in the metabolic transformation occurring in cancer cells and in targeting metabolic enzymes for cancer therapy. 2-4 However, the discovery of dysregulated metabolism in tumors dates back to the work of Otto Warburg in the 1920s. Warburg observed that cancer cells exhibit elevated glycolysis and that much of the generated pyruvate is fermented to lactate rather than feed to the TCA cycle and used for oxidative phosphorylation. 5,6 This phenomenon occurs under anaerobic and even under aerobic conditions ("aerobic glycolysis").A second change that occurs in central metabolism of many cancer cells is the alteration of glutamine metabolism. 7-9 Glutamine can be used to replenish the TCA cycle instead of glucose and feed in carbon and nitrogen for synthesis of nucleotides, several amino acids and glutathione. Further, glutamine can be used for energy production and in transformed cultured cells glutamine driven oxidative phosphorylation was recently shown to be the main source of

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Glutamine Sensitivity Analysis Identifies the xCT Antiporter as a Common Triple-Negative Breast Tumor Therapeutic Target

Cited by 465 publications

References 56 publications

Chemotherapy triggers HIF-1–dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype

Chemotherapy triggers HIF-1–dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

Glutamate enrichment as new diagnostic opportunity in breast cancer

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