MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer

Venkateswaran, Niranjan; Lafita-Navarro, M. Carmen; Hao, Yi; Kilgore, Jessica A.; Perez‐Castro, Lizbeth; Braverman, Jonathan; Borenstein‐Auerbach, Nofit; Kim, Min; Lesner, Nicholas P.; Mishra, Prashant; Brabletz, Thomas; Shay, Jerry W.; DeBerardinis, Ralph J.; Williams, Noelle S.; Yılmaz, Ömer H.; Conacci‐Sorrell, Maralice

doi:10.1101/gad.327056.119

Cited by 150 publications

(176 citation statements)

References 73 publications

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“…In colonic cells, MYC promotes the expression of the tryptophan transporters (SLC7A5 and SLC1A5) and enzyme arylformamidase in the kynurenine pathway, thereby driving the conversion of tryptophan into kynurenine. 34 Of note, high levels of kynurenine can increase the proliferation and migratory capacity of cancer cells, and help tumors escape immune surveillance. 35 In addition to MYC, HIF-2α, the Hippo pathway effectors, the hormone receptors, and the stress response factor ATF4 were shown to upregulate SLC7A5 and/or SLC43A1 expression in multiple cancer types, including clear cell renal carcinoma, hepatocellular carcinoma, breast and prostate cancers, [36][37][38][39][40] which leads to elevated EAA uptake and aggressive tumor progression.…”

Section: Myc Regulation Of Glucose Metabolismmentioning

confidence: 99%

Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat

Dong

Liu

et al. 2020

Sig Transduct Target Ther

208

169

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Cancer cells must rewire cellular metabolism to satisfy the demands of unbridled growth and proliferation. As such, most human cancers differ from normal counterpart tissues by a plethora of energetic and metabolic reprogramming. Transcription factors of the MYC family are deregulated in up to 70% of all human cancers through a variety of mechanisms. Oncogenic levels of MYC regulates almost every aspect of cellular metabolism, a recently revisited hallmark of cancer development. Meanwhile, unrestrained growth in response to oncogenic MYC expression creates dependency on MYC-driven metabolic pathways, which in principle provides novel targets for development of effective cancer therapeutics. In the current review, we summarize the significant progress made toward understanding how MYC deregulation fuels metabolic rewiring in malignant transformation.

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Section: Myc Regulation Of Glucose Metabolismmentioning

confidence: 99%

Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat

Dong

Liu

et al. 2020

Sig Transduct Target Ther

208

169

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“…Finally, we note the presence in this cluster of dodecanedioic acid metabolite. The accumulation of this metabolite is associated with an impairment of fatty acid oxidation at the carnitine palmitoyl transferase (CPT) level 28 , an effect in line with the observed overall reduction of acylcarnitine pools.…”

Section: Biological Effects Of Exposure To Dphp Through Metabolomics mentioning

confidence: 57%

“…Finally, we noticed that the lowest DPhP concentration reduced the expression of genes related to the tryptophan and the xenobiotic metabolism ( Figure 6D). This was intriguing since tryptophan metabolites have been connected to aryl metabolism and the xenobiotic receptor AHR 28,29 . To improve sample clustering, we then tested by OPLS-DA all possible combinations able to discriminate our 4 groups of replicates, using the control replicates as negative controls.…”

Section: Biological Effects Of Dphp Exposure Through Transcriptomic Amentioning

confidence: 99%

In vivocharacterisation of the toxicological properties of DPhP, one of the main degradation products of aryl phosphate esters

Selmi-Ruby

Marín-Sáez

Fildier

et al. 2019

Preprint

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25Conclusions: 57 Our results suggest that in mice, the effects of chronic exposure to DPhP, even at a low dose, are 58 not negligible. Fatty acid metabolism in the liver in particular is essential for controlling fast and 59 feast periods with adverse consequences on the overall physiology. Therefore, the impact of DPhP 60 on circulating fat, cardiovascular and metabolic disease incidence deserves, in light of our results, 61 further investigations. 62 63 3 1. Introduction 64 Di-phenyl phosphate (DPhP) has been used as a main biomarker for assessing exposure to aryl 65 phosphate esters (APEs), especially tri-phenyl phosphate (TPhP), a molecule suspected of 66 presenting human health hazards. However, this degradation compound can be produced from 67 several APEs including ethylhexyl di-phenyl phosphate (EHDPhP) or the resorcinol 68 bis(diphenyl phosphate) (RDP) 1,2 and tert-butylphenyl diphenyl phosphate (BPDP) 3 . Moreover, 69DPhP itself is largely present in the environment worldwide 4-8 , either owing to its 70 spontaneous/microorganism production from known APEs 5,9 , or to its direct use in industry 10 . 71Most APEs are used as flame retardants. They are added to consumer products and raw 72 materials to delay combustion and meet flammability standards such as the ISO/TC92 Fire 73 Safety, TC89 Fire Hazard existing in Europe. Moreover, unlike other flame retardants, TPhP 74 and EHDPhP are also largely used as plasticizer and lubricants in hydraulic fluids, rubber, 75 paints, textile coatings, food packaging and PVC, drastically increasing their presence in the 76 environment. These compounds are not usually covalently linked to plastic materials and can 77 easily leach into the environment 11 . High vapour pressure of TPhP is also likely to facilitate its 78 release in the air once it is freed from its original material 12 . Not surprisingly, TPhP and 79 EHDPhP are thus ubiquitous components of the human indoor environment where its sources 80 and exposure pathways are quite diverse and heterogeneous with regards to other flame 81 retardants. Indeed, TPhP and EHDPhP quantification in food, house dust, water or air has 82systematically demonstrated their presence in these very different matrices raising awareness 83 on the safety of these compounds [4][5][6][7][8]12,13 . A study characterising the direct biological effects of 84 DPhP and their relationship to TPhP exposure thus appeared to be of particular relevance to 85 better define the effects and mechanisms of action associated with exposure to APEs in a more 86 comprehensive way. 87 105 correlated with TPhP levels present in the same environment 4 , hence raising concerns about 106 these potentially hazardous molecules for human health. 107The complexity of the routes of exposure described above can cast doubts as to the 108 relevance of in vitro and in vivo studies describing the toxicities associated with APEs such as 109 the TPhP. For instance, very high doses of TPhP administered via oral gavage (300 mg/kg/day) 110 in adult mice 21 or through...

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“…While it has been shown convincingly that SLC1A5, SLC7A5, SLC7A11, and SLC6A14 are all up-regulated in specific cancer types, molecular mechanisms underlying this up-regulation remain to be explored in greater detail. With regard to SLC1A5 and SLC7A5, the oncogene MYC appears to be at least one of the drivers of up-regulation [44,45]. In the present study, we investigated the molecular mechanism associated with the up-regulation of SLC6A14 in colon cancer.…”

Section: Discussionmentioning

confidence: 95%

SLC6A14, a Na+/Cl−-coupled amino acid transporter, functions as a tumor promoter in colon and is a target for Wnt signaling

Sikder

Sivaprakasam

Brown

et al. 2020

Biochemical Journal

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SLC6A14 is a Na+/Cl−-coupled transporter for neutral and cationic amino acids. It is expressed at basal levels in the normal colon but is up-regulated in colon cancer. However, the relevance of this up-regulation to cancer progression and the mechanisms involved in the up-regulation remain unknown. Here, we show that SLC6A14 is essential for colon cancer and that its up-regulation involves, at least partly, Wnt signaling. The up-regulation of the transporter is evident in most human colon cancer cell lines and also in a majority of patient-derived xenografts. These findings are supported by publicly available TCGA (The Cancer Genome Atlas) database. Treatment of colon cancer cells with α-methyltryptophan (α-MT), a blocker of SLC6A14, induces amino acid deprivation, decreases mTOR activity, increases autophagy, promotes apoptosis, and suppresses cell proliferation and invasion. In xenograft and syngeneic mouse tumor models, silencing of SLC6A14 by shRNA or blocking its function by α-MT reduces tumor growth. Similarly, the deletion of Slc6a14 in mice protects against colon cancer in two different experimental models (inflammation-associated colon cancer and genetically driven colon cancer). In colon cancer cells, expression of the transporter is reduced by Wnt antagonist or by silencing of β-catenin whereas Wnt agonist or overexpression of β-catenin shows the opposite effect. Finally, SLC6A14 as a target for β-catenin is confirmed by chromatin immunoprecipitation. These studies demonstrate that SLC6A14 plays a critical role in the promotion of colon cancer and that its up-regulation in cancer involves Wnt signaling. These findings identify SLC6A14 as a promising drug target for the treatment of colon cancer.

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MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer

Cited by 150 publications

References 73 publications

Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat

Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat

In vivocharacterisation of the toxicological properties of DPhP, one of the main degradation products of aryl phosphate esters

SLC6A14, a Na+/Cl−-coupled amino acid transporter, functions as a tumor promoter in colon and is a target for Wnt signaling

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