Quantitative proteomic analysis of mitochondrial proteins reveals prosurvival mechanisms in the perpetuation of radiation-induced genomic instability

Thomas, Stefani N.; Waters, Katrina M.; Morgan, William F.; Yang, Austin J.; Baulch, Janet E.

doi:10.1016/j.freeradbiomed.2012.03.025

Cited by 13 publications

(15 citation statements)

References 41 publications

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“…These analyses demonstrate significant enrichment of pathways related to oxidative stress, mitochondria and cellular metabolism. While the CS9 and LS12 clones showed the fewest common mRNA changes as a pair, these are probably the two best characterized clones with respect to documentation of persistent oxidative stress and mitochondrial dysfunction [8] , [9] , [11] , [39] , [41] . When evaluated independently in a separate proteomics study the LS12 clone had significant enrichment for electron transport chain and cellular redox homeostasis pathway proteins, and some of those genes were shown to be under epigenetic regulation by miR [11] .…”

Section: Discussionmentioning

confidence: 99%

Genetic and Epigenetic Changes in Chromosomally Stable and Unstable Progeny of Irradiated Cells

et al. 2014

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Radiation induced genomic instability is a well-studied phenomenon, the underlying mechanisms of which are poorly understood. Persistent oxidative stress, mitochondrial dysfunction, elevated cytokine levels and epigenetic changes are among the mechanisms invoked in the perpetuation of the phenotype. To determine whether epigenetic aberrations affect genomic instability we measured DNA methylation, mRNA and microRNA (miR) levels in well characterized chromosomally stable and unstable clonally expanded single cell survivors of irradiation. While no changes in DNA methylation were observed for the gene promoters evaluated, increased LINE-1 methylation was observed for two unstable clones (LS12 and CS9) and decreased Alu element methylation was observed for the other two unstable clones (115 and Fe5.0–8). These relationships also manifested for mRNA and miR expression. mRNA identified for the LS12 and CS9 clones were most similar to each other (261 mRNA), while the 115 and Fe5.0–8 clones were more similar to each other, and surprisingly also similar to the two stable clones, 114 and 118 (286 mRNA among these four clones). Pathway analysis showed enrichment for pathways involved in mitochondrial function and cellular redox, themes routinely invoked in genomic instability. The commonalities between the two subgroups of clones were also observed for miR. The number of miR for which anti-correlated mRNA were identified suggests that these miR exert functional effects in each clone. The results demonstrate significant genetic and epigenetic changes in unstable cells, but similar changes are almost as equally common in chromosomally stable cells. Possible conclusions might be that the chromosomally stable clones have some other form of instability, or that some of the observed changes represent a sort of radiation signature and that other changes are related to genomic instability. Irrespective, these findings again suggest that a spectrum of changes both drive genomic instability and permit unstable cells to persist and proliferate.

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Section: Discussionmentioning

confidence: 99%

Genetic and Epigenetic Changes in Chromosomally Stable and Unstable Progeny of Irradiated Cells

et al. 2014

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“…While both acute and chronic irradiation had an effect on cell proliferation, only chronic irradiation induced significant changes in metabolism. Chronic irradiation of all glioma lines elicited significant and persistent increases in oxidative stress, possibly reflective of perturbations to mitochondrial electron transport function along with compensatory upregulation of the tricarboxylic acid cycle [Dayal et al, ; Thomas et al, ]. Radiation‐induced metabolic changes may also signal an increase in glycolytic flux, and changes in the epigenetic regulation of redox sensitive pathways promoting cellular reprogramming.…”

Section: Discussionmentioning

confidence: 99%

Irradiation of primary human gliomas triggers dynamic and aggressive survival responses involving microvesicle signaling

Baulch

Geidzinski

Tran

et al. 2015

Environ and Mol Mutagen

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Malignant gliomas are heterogeneous populations of dynamically interacting cells. Genomic and transcriptional changes define this cellular hierarchy and allow certain tumor cells to co-opt metabolic machinery and adopt gene expression profiles that promote cellular reprogramming. Resultant expansion of privileged subpopulations can then rapidly adapt to microenvironmental stress that ultimately influence tumor response to therapeutic intervention. In this study, primary gliomas were subjected to acute or chronic irradiation and analyzed for changes in survival parameters, oxidative stress, gene expression, and cell invasion before and after treatment with secreted microvesicles isolated from irradiated and nonirradiated glioma cells. We found that primary gliomas exposed to ionizing radiation undergo metabolic changes that increase oxidative stress, alter gene expression, and affect the contents of and response to cellular secreted microvesicles. Radiation-induced changes were exacerbated under chronic as compared to acute irradiation paradigms and promoted cellular reprogramming through enhanced expression of key transcription factors and regulators involved in differentiation and pluripotency (SOX2, POU3F2, SALL2, OLIG2, NANOG, POU5F1v1, MSI1). Irradiation also affected changes in paracrine signaling mediated by cellular secreted microvesicles that significantly altered target cell phenotype. Primary gliomas treated with microvesicles exhibited increased radioresistance and treatment with microvesicles from chronically irradiated gliomas promoted invasion via induction of increased matrix metalloproteinase II activity. Together, our data describe a complex radiation response of primary glioma cells involving metabolic and transcriptional changes that alter radiation sensitivity and induce invasive behavior. These important changes can contribute to tumor growth and recurrence, and confound interventions designed to forestall disease progression. Environ. Mol. Mutagen. 57:405-415, 2016. © 2015 Wiley Periodicals, Inc.

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“…In the LS12 human–hamster hybrid cell line, oxidative stress and genomic instability induced by radiation were correlated with mitochondrial dysfunctions. The mass spectrometric analysis of the FFE‐purified mitochondria revealed an enhanced number of proteins suggesting that the LS12 cells might have adapted mechanisms that allow survival under suboptimal conditions of oxidative stress . During induction of cell death, mitochondria undergo a stage of permeability transition leading to the disruption of the outer mitochondrial membrane.…”

Section: Purification Of Mitochondriamentioning

confidence: 99%

Preparative free‐flow electrophoresis, a versatile technology complementing gradient centrifugation in the isolation of highly purified cell organelles

Islinger

Wildgruber²,

Völkl

2018

Electrophoresis

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Free-flow electrophoresis (FFE) exploits differences in the overall charge of bio-particles separating cells, organelles, macromolecules, ions, etc. according to their distinct electrophoretic mobility and isoelectric point (pI) values. Indeed, around a neutral pH organelles usually exhibit a negative surface charge, migrating in an electric field from the cathode toward the anode. Since its introduction more than five decades ago by Barrollier et al., Z. Naturforsch. 1958, 13b, 745-755 and Hannig, Z. Anal. Chem. 1961, 181, 244-254, FFE has become an established analytical and preparative separation method for the isolation of a variety of organelles. Particularly, in sophisticated, multistep separating processes to separate subpopulations of organelles, it has gained, meanwhile, a position as a versatile technology and essential element. Relying on the distinct surface charges instead of buoyant densities of cell organelles, the FFE technology is best supporting a preceding centrifugation-based fractionation of subcellular compartments in the second dimension. In the following review, the two-step isolation and purification of subpopulations of classic animal and plant cell organelles will be mainly exemplified.

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Quantitative proteomic analysis of mitochondrial proteins reveals prosurvival mechanisms in the perpetuation of radiation-induced genomic instability

Cited by 13 publications

References 41 publications

Genetic and Epigenetic Changes in Chromosomally Stable and Unstable Progeny of Irradiated Cells

Genetic and Epigenetic Changes in Chromosomally Stable and Unstable Progeny of Irradiated Cells

Irradiation of primary human gliomas triggers dynamic and aggressive survival responses involving microvesicle signaling

Preparative free‐flow electrophoresis, a versatile technology complementing gradient centrifugation in the isolation of highly purified cell organelles

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