Metabolic reprogramming of the tumor

Ferreira, Leonardo M. R.; Hebrant, Aline; Dumont, Jacques Emile

doi:10.1038/onc.2011.576

Cited by 111 publications

(90 citation statements)

References 163 publications

(196 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…53 Our results, as well as previous observations by Cavill et al, 32 suggest that metabolism, and the nucleotide salvage pathway in particular, can play a pivotal role.…”

Section: ■ Discussionsupporting

confidence: 77%

A Systems Oncology Approach Identifies NT5E as a Key Metabolic Regulator in Tumor Cells and Modulator of Platinum Sensitivity

et al. 2015

View full text Add to dashboard Cite

Altered metabolism in tumor cells is required for rapid proliferation but also can influence other phenotypes that affect clinical outcomes such as metastasis and sensitivity to chemotherapy. Here, a genome-wide association study (GWAS)-guided integration of NCI-60 transcriptome and metabolome data identified ecto-5′-nucleotidase (NT5E or CD73) as a major determinant of metabolic phenotypes in cancer cells. NT5E expression and associated metabolome variations were also correlated with sensitivity to several chemotherapeutics including platinum-based treatment. NT5E mRNA levels were observed to be elevated in cells upon in vitro and in vivo acquisition of platinum resistance in ovarian cancer cells, and specific targeting of NT5E increased tumor cell sensitivity to platinum. We observed that tumor NT5E levels were prognostic for outcomes in ovarian cancer and were elevated after treatment with platinum, supporting the translational relevance of our findings. In this work, we integrated and analyzed a plethora of public data, demonstating the merit of such a systems oncology approach for the discovery of novel players in cancer biology and therapy. We experimentally validated the main findings of the NT5E gene being involved in both intrinsic and acquired resistance to platinum-based drugs. We propose that the efficacy of conventional chemotherapy could be improved by NT5E inhibition and that NT5E expression may be a useful prognostic and predictive clinical biomarker.

show abstract

“…53 Our results, as well as previous observations by Cavill et al, 32 suggest that metabolism, and the nucleotide salvage pathway in particular, can play a pivotal role.…”

Section: ■ Discussionsupporting

confidence: 77%

A Systems Oncology Approach Identifies NT5E as a Key Metabolic Regulator in Tumor Cells and Modulator of Platinum Sensitivity

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Tumour cells adapt to various microenvironments and energy-related challenges by switching between glycolysis, glutaminolysis, and mitochondrial metabolism (Daye and Wellen, 2012; Ferreira et al , 2012). The metabolic reprogramming provides the cellular energy required for increased cancer growth and proliferation (Jones and Schulze, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Metabolic phenotype and growth pattern in tumour cells, especially within solid tumours, are totally dependent on several microenvironmental factors including hypoxia, nutrient availability, and angiogenesis (Dang, 2012; Metallo et al , 2012). Tumour cells cope with changing energetic requirements and demands for maintenance and growth via metabolic reprogramming through altered signalling and facilitation of unique metabolic strategies (Ferreira et al , 2012; Ward and Thompson, 2012). One of the first biochemical differences observed in tumour cells as compared with normal cells is a shift in energy metabolism from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect (Gatenby and Gillies, 2004; Vander Heiden et al , 2009).…”

mentioning

confidence: 99%

Profiling and targeting of cellular bioenergetics: inhibition of pancreatic cancer cell proliferation

et al. 2014

View full text Add to dashboard Cite

Background:Targeting both mitochondrial bioenergetics and glycolysis pathway is an effective way to inhibit proliferation of tumour cells, including those that are resistant to conventional chemotherapeutics.Methods:In this study, using the Seahorse 96-well Extracellular Flux Analyzer, we mapped the two intrinsic cellular bioenergetic parameters, oxygen consumption rate and proton production rate in six different pancreatic cancer cell lines and determined their differential sensitivity to mitochondrial and glycolytic inhibitors.Results:There exists a very close relationship among intracellular bioenergetic parameters, depletion of ATP and anti-proliferative effects (inhibition of colony-forming ability) in pancreatic cancer cells derived from different genetic backgrounds treated with the glycolytic inhibitor, 2-deoxyglucose (2-DG). The most glycolytic pancreatic cancer cell line was exquisitely sensitive to 2-DG, whereas the least glycolytic pancreatic cancer cell was resistant to 2-DG. However, when combined with metformin, inhibitor of mitochondrial respiration and activator of AMP-activated protein kinase, 2-DG synergistically enhanced ATP depletion and inhibited cell proliferation even in poorly glycolytic, 2-DG-resistant pancreatic cancer cell line. Furthermore, treatment with conventional chemotherapeutic drugs (e.g., gemcitabine and doxorubicin) or COX-2 inhibitor, celecoxib, sensitised the cells to 2-DG treatment.Conclusions:Detailed profiling of cellular bioenergetics can provide new insight into the design of therapeutic strategies for inhibiting pancreatic cancer cell metabolism and proliferation.

show abstract

“…Metabolic reprogramming results not only from the hypoxia of the tumor but also from oncogenic events, as it also occurs in fully oxygenated leukemic cells [58]. Hypoxia itself causes EMT [59] and induces multidrug resistance [60] as well as other hallmarks [61,62]. Phenotypic characteristics themselves may modulate several hallmarks, as when hypoxia promotes immunological tolerance and angiogenesis [63].…”

Section: Opinionmentioning

confidence: 98%