Dataset Information

Radiation resistance comparable to natural extremophiles achieved through experimental evolution

ABSTRACT: Recent human exploitation of high-level sources of ionizing radiation (IR) has generated a corresponding need to understand the effects of IR on living systems. Part of that research has focused on the astonishing capacity of some organisms to survive extraordinary levels of IR exposure. Using experimental evolution, we have generated populations of Escherichia coli with an IR resistance phenotype comparable to the extremophile Deinococcus radiodurans. Every aspect of cell physiology is affected. Cellular isolates exhibit approximately 1,000 base pair changes plus major genomic and proteomic alterations. The extreme IR resistance phenotype, stable without selection for at least 100 generations, has no single molecular origin. Defined and probable contributions include alterations in cellular systems involved in DNA repair, amelioration of reactive oxygen species, Fe metabolism and repair of iron-sulfur centers, DNA packaging, intermediary metabolism, and more. Some contributions to IR resistance are highly dependent on both genomic and environmental context.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Deinococcus Radiodurans Escherichia Coli

SUBMITTER: Benjamin Minkoff

LAB HEAD: Michael R Sussman

PROVIDER: PXD024784 | Pride | 2021-09-10

REPOSITORIES: Pride

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Publications

Proteome Damage Inflicted by Ionizing Radiation: Advancing a Theme in the Research of Miroslav Radman.

Bruckbauer Steven T ST Minkoff Benjamin B BB Sussman Michael R MR Cox Michael M MM

Cells 20210420 4

Oxidative proteome damage has been implicated as a major contributor to cell death and aging. Protein damage and aging has been a particular theme of the recent research of Miroslav Radman. However, the study of how cellular proteins are damaged by oxidative processes is still in its infancy. Here we examine oxidative changes in the proteomes of four bacterial populations-wild type <i>E. coli</i>, two isolates from <i>E. coli</i> populations evolved for high levels of ionizing radiation (IR) res ...[more]

PMID: 33924085

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Project description:Insulin-like growth factor receptor-1 (IGF-1R) inhibition could be a relevant therapeutic approach in small cell lung cancer (SCLC) given the importance of an IGF-1R autocrine loop and its role in DNA damage repair processes. We assessed IGF-1R and pAkt protein expression in 83 SCLC human specimens. The efficacy of R1507 (a monoclonal antibody directed against IGF-1R) alone or combined with cisplatin or ionizing radiation (IR) was evaluated in H69, H146 and H526 cells in vitro and in vivo. Innovative genomic and functional approaches were conducted to analyze the molecular behavior under the different treatment conditions. A total of 53% and 37% of human specimens expressed IGF-1R and pAkt, respectively. R1507 demonstrated single agent activity in H146 and H526 cells but not in H69 cells. R1507 exhibited synergistic effects with both Cisplatin and IR in vitro. The triple combination R1507-Cisplatin-IR led to a dramatic delay in tumor growth compared to Cisplatin-IR in H526 cells. Analyzing the apparent absence of antitumoral effect of R1507 alone in vivo, we observed a transient reduction of IGF-1R staining intensity in vivo, concomitant to the activation of multiple cell surface receptors and intracellular proteins involved in proliferation, angiogenesis and survival. Finally, we identified that the nucleotide excision repair pathway (NER) was mediated after exposure to R1507-CDDP and R1507-IR in vitro and in vivo. In conclusion, adding R1507 to the current standard Cisplatin-IR doublet reveals remarkable chemo- and radiosensitizing effects in selected SCLC models and warrants to be investigated in the clinical setting. We used microarrays to investigate the effect of IGF-1R targetting on the global gene expression. Gene expression data from H526 xenografts under various treatment and time conditions Total mRNA from 33 NCI-H526 SCLC (small-cell lung cancer) xenografts was hybridized to Affymetrix HGU133 Plus 2.0 expression arrays. Log2 gene expression values were calculated using RMA. (A) To identify the molecular mechanisms involved in the response to R1507 alone along the treatment time, we performed global gene expression profiling in H526 xenografts at the following time points: baseline (vehicle), R1507 day 1 and R1507 day 7. (B) To identify the molecular mechanisms involved in the response to CDDP- and IR-R1507 combinations, we performed global gene expression profiling on mice bearing H526 xenografts treated with the following treatment conditions: vehicle, R1507 CDDP, IR, CDDP-R1507 and IR-R1507.

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Dataset Information

Radiation resistance comparable to natural extremophiles achieved through experimental evolution

Publications

Proteome Damage Inflicted by Ionizing Radiation: Advancing a Theme in the Research of Miroslav Radman.

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