mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy

Weiler, Markus; Blaes, Jonas; Pusch, Stefan; Sahm, Felix; Czabanka, Marcus; Luger, Sebastian; Bunse, Lukas; Solecki, Gergely; Eichwald, Viktoria; Jugold, Manfred; Hodecker, Sibylle; Osswald, Matthias; Meisner, Christoph; Hielscher, Thomas; Rübmann, Petra; Pfenning, P. N.; Ronellenfitsch, Michael; Kempf, Tore; Schnölzer, Martina; Abdollahi, Amir; Läng, Florian; Bendszus, Martin; Deimling, Andreas von; Winkler, Frank; Weller, Michael; Vajkoczy, Peter; Platten, Michael; Wick, Wolfgang

doi:10.1073/pnas.1314469111

Cited by 159 publications

(155 citation statements)

References 24 publications

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“…1A). Higher NDRG1 expression has been associated with enhanced DNA repair through increased MGMT protein stability/activity (Weiler et al ., 2014). We therefore measured NDRG1 and MGMT protein expression in liver, skeletal muscle (upper leg), and kidney from our three slow‐aging mice models fed ad lib.…”

Section: Resultsmentioning

confidence: 99%

“…It have been suggested that MGMT may play a role in regulating mouse lifespan (Meira et al ., 2014), but it is not known whether long‐lived mice, such as Snell, GHRKO, and PAPPA‐KO, have altered expression of MGMT. Higher expression of NDRG1, a protein of unknown function, can promote MGMT protein stability and activity in human glioma cells by mechanisms that include protein interactions and preferential translation (Smalley et al ., 2014; Weiler et al ., 2014). Therefore, understanding the signaling pathways regulating MGMT and NDRG1 may provide insights into resistance to DNA damage, chemotherapy, and the aging process.…”

Section: Introductionmentioning

confidence: 99%

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mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Dominick

Bowman

et al. 2016

Aging Cell

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SummaryStudies of the mTOR pathway have prompted speculation that diminished mTOR complex‐1 (mTORC1) function may be involved in controlling the aging process. Our previous studies have shown diminished mTORC1 activity in tissues of three long‐lived mutant mice: Snell dwarf mice, growth hormone receptor gene disrupted mice (GHRKO), and in this article, mice deficient in the pregnancy‐associated protein‐A (PAPPA‐KO). The ways in which lower mTOR signals slow aging and age‐related diseases are, however, not well characterized. Here, we show that Snell, GHKRO, and PAPPA‐KO mice express high levels of two proteins involved in DNA repair, O‐6‐methylguanine‐DNA methyltransferase (MGMT) and N‐myc downstream‐regulated gene 1 (NDRG1). Furthermore, we report that lowering mTOR enhances MGMT and NDRG1 protein expression via post‐transcriptional mechanisms. We show that the CCR4‐NOT complex, a post‐transcriptional regulator of gene expression, is downstream of the mTORC1 pathway and may be responsible for the upregulation of MGMT and NDRG1 in all three varieties of long‐lived mice. Our data thus suggest a novel link between DNA repair and mTOR signaling via post‐transcriptional regulation involving specific alteration in the CCR4‐NOT complex, whose modulation could control multiple aspects of the aging process.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Dominick

Bowman

et al. 2016

Aging Cell

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“…These cells in turn may be sensitized by treatment with bone morphogenetic protein 2 (BMP2), which can down-regulate HIF-1α-mediated MGMT induction [45]. Induction of resistance may also be conferred by the hypoxia-and steroid-inducible N-myc downstream-regulated gene (NDRG1), which binds to and thus probably sustains action of MGMT [46]. Recent studies addressed a further level of MGMT regulation through direct binding of specific miRNAs to the 3'-UTR of MGMT transcripts, which may lead to decreased mRNA stability and/or reduced protein translation [47].…”

Section: Regulation Of Expression and Function Of Mgmtmentioning

confidence: 99%

MGMT testing—the challenges for biomarker-based glioma treatment

et al. 2014

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Many patients with malignant gliomas do not respond to alkylating agent chemotherapy. Alkylator resistance of glioma cells is mainly mediated by the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT). Epigenetic silencing of the MGMT gene by promoter methylation in glioma cells compromises this DNA repair mechanism and increases chemosensitivity. MGMT promoter methylation is, therefore, a strong prognostic biomarker in paediatric and adult patients with glioblastoma treated with temozolomide. Notably, elderly patients (>65-70 years) with glioblastoma whose tumours lack MGMT promoter methylation derive minimal benefit from such chemotherapy. Thus, MGMT promoter methylation status has become a frequently requested laboratory test in neuro-oncology. This Review presents current data on the prognostic and predictive relevance of MGMT testing, discusses clinical trials that have used MGMT status to select participants, evaluates known issues concerning the molecular testing procedure, and addresses the necessity for molecular-context-dependent interpretation of MGMT test results. Whether MGMT promoter methylation testing should be offered to all individuals with glioblastoma, or only to elderly patients and those in clinical trials, is also discussed. Justifications for withholding alkylating agent chemotherapy in patients with MGMT-unmethylated glioblastomas outside clinical trials, and the potential role for MGMT testing in other gliomas, are also discussed. What is the role for MGMT testing in other gliomas? The answers to these issues depend not only on data from controlled clinical trials, but also on the availability of alternative treatment options to alkylating agents treatment, as well as on the access to molecular testing and its sensitivity and specificity.

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“…Cell proliferation (Cell Index) was checked using the xCELLigence Real-Time Cell Analyzer (RTCA) instrument according to the instructions of the supplier (Roche Applied Science and ACEA Biosciences, San Diego, CA, USA). This system has been extensively used in other studies (8,9). The xCELLigence system can quantify the electrical impedance across electrodes at the bottom of each well of the tissue culture plates.…”

Section: Drug Cytotoxicity Analysis and Real Time Analysis Of Cell Prmentioning

confidence: 99%

Silencing of ECHDC1 inhibits growth of gemcitabine‑resistant bladder cancer cells

et al. 2017

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Abstract. Combined gemcitabine and cisplatin (GC) treatment is a first line chemotherapy for bladder cancer. However, acquired resistance to GC has been a major problem. To address the mechanism of gemcitabine resistance, and to identify potential biomarkers or target proteins for its therapy, we aimed to identify candidate proteins associated with gemcitabine resistance using proteomic analysis. We established gemcitabine-resistant human bladder cancer cell lines (UMUC3GR and HT1376GR) from gemcitabine-sensitive human bladder cancer cell lines (UMUC3 and HT1376). We compared the protein expression of parental and gemcitabine-resistant cell lines using isobaric tags for relative and absolute quantification (iTRAQ) and liquid chromatography tandem mass spectrometry. Among the identified proteins, ethylmalonyl-CoA decarboxylase (ECHDC1) expression was significantly increased in both of the gemcitabine-resistant cell lines compared to the respective parental cell lines. Silencing of ECHDC1 reduced ECHDC1 expression and significantly inhibited the proliferation of UMUC3GR cells. Furthermore, silencing of ECHDC1 induced upregulation of p27, which is critical for cell cycle arrest in the G1 phase, and induced G1 arrest. In conclusion, ECHDC1 expression is increased in gemcitabine-resistant bladder cancer cells, and is involved in their cell growth. ECHDC1, which is a metabolite proofreading enzyme, may be a novel potential target for gemcitabine-resistant bladder cancer therapy.

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mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy

Cited by 159 publications

References 24 publications

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

MGMT testing—the challenges for biomarker-based glioma treatment

Silencing of ECHDC1 inhibits growth of gemcitabine‑resistant bladder cancer cells

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