Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function

Viale, Andrea; Pettazzoni, Piergiorgio; Lyssiotis, Costas A.; Ying, Haoqiang; Sánchez, Nora; Marchesini, Matteo; Carugo, Alessandro; Green, Tessa; Seth, Sahil; Giuliani, Virginia; Kost‐Alimova, Maria; Muller, Florian L.; Colla, Simona; Nezi, Luigi; Genovese, Giannicola; Deem, Angela K.; Kapoor, Avnish; Brunetto, Emanuela; Kang, Ya’an; Yuan, Min; Asara, John M.; Wang, Y. Alan; Heffernan, Timothy P.; Kimmelman, Alec C.; Wang, Huamin; Fleming, Jason B.; Cantley, Lewis C.; DePinho, Ronald A.; Draetta, Giulio

doi:10.1038/nature13611

Cited by 1,059 publications

(1,092 citation statements)

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“…18,19 Other research based on the selective toxicity of metformin toward cancer stem cells (CSCs), however, supports a "reverse Warburg effect, " arguing that CSCs are more dependent on oxidative phosphorylation. 15,22,23 Viale et al 20 demonstrated that the surviving cancer cells that are responsible for tumor relapse have features of CSCs and depend on oxidative phosphorylation for their survival.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, refractory cells, characterized by their stem cell-like properties, are more dependent on oxidative phosphorylation. [18][19][20] Many studies have shown that inhibition of either glycolysis or oxidative phosphorylation is effective to decrease proliferation and invasion of cancer cells. [21][22][23] However, exploiting the idea that simultaneous inhibition of multiple metabolic pathways might be a more effective cancer treatment, several researchers have shown that deprivation of tumor bioenergetics through inhibition of multiple energy pathways could be an effective new therapeutic approach for various human tumors 8,24 -an idea that has not been fully evaluated in a GBM-TS model.…”

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confidence: 99%

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Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Kim

Lee

et al. 2016

NEUONC

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Background. Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various human tumors. However, this idea has not been evaluated in glioblastoma (GBM). We hypothesized that dual inhibition of glycolysis and oxidative phosphorylation could effectively suppress GBM tumorspheres (TS). Methods. Effects of 2-deoxyglucose (2DG) and metformin, alone and in combination, on GBM-TS were evaluated. Viability, cellular energy metabolism status, stemness, invasive properties, and GBM-TS transcriptomes were examined. In vivo efficacy was tested in a mouse orthotopic xenograft model. Results. GBM-TS viability was decreased by the combination of 2DG and metformin. ATP assay and PET showed that cellular energy metabolism was also decreased by this combination. Sphere formation, expression of stemnessrelated proteins, and invasive capacity of GBM-TS were also significantly suppressed by combined treatment with 2DG and metformin. A transcriptome analysis showed that the expression levels of stemness-and epithelial mesenchymal transition-related genes were also significantly downregulated by combination of 2DG and metformin. Combination treatment also prolonged survival of tumor-bearing mice and decreased invasiveness of GBM-TS. Conclusion. The combination of 2DG and metformin effectively decreased the stemness and invasive properties of GBM-TS and showed a potential survival benefit in a mouse orthotopic xenograft model. Our findings suggest that targeting TS-forming cells by this dual inhibition of cellular bioenergetics warrants expedited clinical evaluation for the treatment of GBM.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Kim

Lee

et al. 2016

NEUONC

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“…Second, select targeting of OxPhostype survival mechanisms may have broader implications for resistance mechanisms that enable tumors to escape inhibition of canonical growth factor signaling, including those initiated by BCR, RAS, and BRAF signaling pathways. 7,52,53 Notably, tigecycline is FDA-approved and is being actively developed for its potential therapeutic benefits in several diseases. 54 Our findings warrant investigation of the therapeutic utility of tigecycline and other inhibitors of the mitochondrial translation pathway in DLBCL and other OxPhos-dependent tumors.…”

Section: Discussionmentioning

confidence: 99%

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

et al. 2016

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Diffuse large B-cell lymphomas (DLBCLs) are a highly heterogeneous group of tumors in which subsets share molecular features revealed by gene expression profiles and metabolic fingerprints. While B-cell receptor (BCR)-dependent DLBCLs are glycolytic, OxPhos-DLBCLs rely on mitochondrial energy transduction and nutrient utilization pathways that provide pro-survival benefits independent of BCR signaling. Integral to these metabolic distinctions is elevated mitochondrial electron transport chain (ETC) activity in OxPhos-DLBCLs compared with BCR-DLBCLs, which is linked to greater protein abundance of ETC components. To gain insights into molecular determinants of the selective increase in ETC activity and dependence on mitochondrial energy metabolism in OxPhos-DLBCLs, we examined the mitochondrial translation pathway in charge of the synthesis of mitochondrial DNA encoded ETC subunits. Quantitative mass spectrometry identified increased expression of mitochondrial translation factors in OxPhos-DLBCL as compared with the BCR subtype. Biochemical and functional assays indicate that the mitochondrial translation pathway is required for increased ETC activity and mitochondrial energy reserves in OxPhos-DLBCL. Importantly, molecular depletion of several mitochondrial translation proteins using RNA interference or pharmacological perturbation of the mitochondrial translation pathway with the FDA-approved inhibitor tigecycline (Tigecyl) is selectively toxic to OxPhos-DLBCL cell lines and primary tumors. These findings provide additional molecular insights into the metabolic characteristics of OxPhosDLBCLs, and mark the mitochondrial translation pathway as a potential therapeutic target in these tumors. Cells adapt their metabolism to satisfy changing biosynthetic and bioenergetic needs.1,2 Investigation of metabolic reprogramming in cancer has provided insights into the metabolic control of proliferation and survival.3-5 Although the initial focus of this field has been aerobic glycolysis (the Warburg effect), 6 increasing evidence points to a complex landscape of tumor metabolic circuitries beyond aerobic glycolysis, including varied contribution of mitochondria to tumor metabolism as well as heterogeneity in fuel utilization pathways. 7-12Diffuse large B-cell lymphomas (DLBCLs) are a genetically heterogeneous group of tumors that can be classified into distinct molecular subtypes based on gene expression profiles. The cell-of-origin (COO) classification defined DLBCL subsets that shared certain components of their RNA profiles with normal germinal center B cells (GCBs) or in vitroactivated B cells (ABCs), and a third undefined subset designated 'type 3'. 13 Using an independent approach, the consensus cluster classification (CCC) framework compared the transcriptional profiles of DLBCL groups with each other without referencing normal B cells. 14 CCC identified tumorintrinsic distinctions in three highly reproducible clusters; the B-cell receptor/proliferation cluster (BCR-DLBCL) showing increased expression of BCR signa...

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“…After oncogene ablation, SCs rely less on glucose and glutamine and more on pyruvate and palmitate to restore TCA cycle intermediates [60]. However, the genetic or pharmacological inhibition of glutamine metabolism sensitizes tumors to ß-lapachone.…”

Section: K-rasmentioning

confidence: 99%

Glutamine at focus: versatile roles in cancer

2015

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Your article is protected by copyright and all rights are held exclusively by International Society of Oncology and BioMarkers (ISOBM).Abstract During the past decade, a heightened understanding of metabolic pathways in cancer has significantly increased. It is recognized that many tumor cells are genetically programmed and have involved an abnormal metabolic state. Interestingly, this increased metabolic autonomy generates dependence on various nutrients such as glucose and glutamine. Both of these components participate in various facets of metabolic activity that allow for energy production, synthesis of biomass, antioxidant defense, and the regulation of cell signaling. Here, we outline the emerging data on glutamine metabolism and address the molecular mechanisms underlying glutamine-induced cell survival. We also discuss novel therapeutic strategies to exploit glutamine addiction of certain cancer cell lines.

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Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function

Cited by 1,059 publications

References 29 publications

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

Glutamine at focus: versatile roles in cancer

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