Metabolic changes in cancer cells upon suppression of MYC

Ansó, Elena; Mullen, Andrew R.; Felsher, Dean W.; Matés, José M.; DeBerardinis, Ralph J.; Chandel, Navdeep S.

doi:10.1186/2049-3002-1-7

Cited by 56 publications

(53 citation statements)

References 35 publications

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“…c-MYC transcriptionally activates the glutamine transporters and glutaminases (29). The role of c-MYC in glutamine addiction has been well studied in glioblastoma (30) and osteosarcoma (10), but its effect on breast cancer metabolism is not well established. Western blot analysis in a panel of cell lines showed that c-MYC levels are higher than normal in 50% of the tumor cells, and c-MYC levels correlated with glutamine dependence and AOA sensitivity, with a Spearman correlation of r = 0.664; P = 0.03 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…High c-MYC alters glutamine catabolism, which significantly enhances glutamine uptake, and shifts glutamine metabolic pathways to maintain redox-balance and fuel energy for cell growth (10), rendering it a novel therapeutic target (11). Aminooxyacetate (AOA) is a general inhibitor of pyridoxal phosphate–dependent enzymes, including transaminases, that are involved in amino acid metabolism and has displayed significant antitumor effects as a single agent in preclinical studies (10, 12, 13). In clinical trials of patients with tinnitus (14, 15) and Huntington’s disease (16), AOA was well tolerated at approximately 1 to 2 mg/kg/d.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Glutamine Metabolism in Breast Cancer with Aminooxyacetate

Korangath

Teo

Sadik

et al. 2015

Clinical Cancer Research

141

113

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Purpose Glutamine addiction in c-MYC–overexpressing breast cancer is targeted by the aminotransferase inhibitor, aminooxyacetate (AOA). However, the mechanism of ensuing cell death remains unresolved. Experimental Design A correlation between glutamine dependence for growth and c-MYC expression was studied in breast cancer cell lines. The cytotoxic effects of AOA, its correlation with high c-MYC expression, and effects on enzymes in the glutaminolytic pathway were investigated. AOA-induced cell death was assessed by measuring changes in metabolite levels by magnetic resonance spectroscopy (MRS), the effects of amino acid depletion on nucleotide synthesis by cell-cycle and bromodeoxyuridine (BrdUrd) uptake analysis, and activation of the endoplasmic reticulum (ER) stress–mediated pathway. Antitumor effects of AOA with or without common chemotherapies were determined in breast cancer xenografts in immunodeficient mice and in a transgenic MMTV-rTtA-TetO-myc mouse mammary tumor model. Results We established a direct correlation between c-MYC overexpression, suppression of glutaminolysis, and AOA sensitivity in most breast cancer cells. MRS, cell-cycle analysis, and BrdUrd uptake measurements indicated depletion of aspartic acid and alanine leading to cell-cycle arrest at S-phase by AOA. Activation of components of the ER stress–mediated pathway, initiated through GRP78, led to apoptotic cell death. AOA inhibited growth of SUM159, SUM149, and MCF-7 xenografts and c-myc–overexpressing transgenic mouse mammary tumors. In MDA-MB-231, AOA was effective only in combination with chemotherapy. Conclusions AOA mediates its cytotoxic effects largely through the stress response pathway. The preclinical data of AOA’s effectiveness provide a strong rationale for further clinical development, particularly for c-MYC–overexpressing breast cancers.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting Glutamine Metabolism in Breast Cancer with Aminooxyacetate

Korangath

Teo

Sadik

et al. 2015

Clinical Cancer Research

141

113

View full text Add to dashboard Cite

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“…426,427 However, it remained unclear whether succinylation of the phenolic hydroxyl group is a critical requirement for observing the antitumor potential of mitochondria-targeted vitamin E analogs. 549 …”

Section: Mitochondria-targeted Therapeutics In the Pre-clinical Momentioning

confidence: 99%

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Zielonka¹,

Joseph²,

et al. 2017

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Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the potentials of cell and mitochondrial membranes, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

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“…In addition, MYC regulates approximately 10% of human genes (Fernandez et al, 2003) and have the ability to promote cellular proliferation and block cellular differentiation. Dysregulation of MYC has been detected in a wide variety of human tumors, such as prostate cancer, breast cancer, and osteogenic sarcoma (Anso et al, 2013;Zhang et al, 2014;Terunuma et al, 2014). For the past few years, MYC genetic variations have received widespread attention, particularly the single nucleotide polymorphism MYC rs9642880 (G>T).…”

Section: Discussionmentioning

confidence: 99%

Association between MYC rs9642880[T] allele and bladder cancer risk: a meta-analysis

Zhao¹,

Qi²,

Yang³

et al. 2015

Genet. Mol. Res.

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ABSTRACT.A single nucleotide polymorphism of MYC rs9642880 (G>T) at the 8q24.1 locus is thought to be associated with bladder cancer risk based on the results of genome-wide association studies, but the results remain inconclusive. To assess the association between rs9642880[T] allele and bladder cancer risk, we performed this meta-analysis including 18 case-control studies and involving 23,084 cases and 97,164 controls. Electronic searches for publications were conducted to determine the association between this variant and prostate cancer in several databases. The last search update was August 4, 2014. We used odds ratios and 95%CIs to evaluate the strength of the associations. The overall results suggested that the rs9642880[T] allele was associated with bladder cancer susceptibility (T vs G, odds ratio = 1.18, 95%CI = 1.14-1.22). In subgroup analysis by ethnicity and source of controls, the risk remained significant. The present meta-analysis suggests that the MYC rs9642880 [T] allele is significantly associated with bladder cancer risk.

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Metabolic changes in cancer cells upon suppression of MYC

Cited by 56 publications

References 35 publications

Targeting Glutamine Metabolism in Breast Cancer with Aminooxyacetate

Targeting Glutamine Metabolism in Breast Cancer with Aminooxyacetate

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Association between MYC rs9642880[T] allele and bladder cancer risk: a meta-analysis

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