External modulators and redox homeostasis: Scenario in radiation-induced bystander cells

Abstract Sugarcane (Saccharum officinarum) is a globally cultivated cash crop whose yield is negatively affected by soil salinity. In this study, we investigated the molecular basis of inducible salt tolerance in M4209, a sugarcane mutant line generated through radiation-induced mutagenesis. Under salt-contaminated field conditions, M4209 exhibited 32% higher cane yield as compared with its salt-sensitive parent, Co86032. In pot experiments, post-sprouting phenotyping indicated that M4209 had significantly greater leaf biomass compared with Co86032 under treatment with 50 mM and 200 mM NaCl. This was concomitant with M4209 having 1.9-fold and 1.6-fold higher K+/Na+ ratios, and 4-fold and 40-fold higher glutathione reductase activities in 50 mM and 200 mM NaCl, respectively, which suggested that it had better ionic and redox homeostasis than Co86032. Transcriptome profiling using RNA-seq indicated an extensive reprograming of stress-responsive modules associated with photosynthesis, transmembrane transport, and metabolic processes in M4209 under 50 mM NaCl stress. Using ranking analysis, we identified Phenylalanine Ammonia Lyase (PAL), Acyl-Transferase Like (ATL), and Salt-Activated Transcriptional Activator (SATA) as the genes most associated with salt tolerance in M4209. M4209 also exhibited photosynthetic rates that were 3–4-fold higher than those of Co86032 under NaCl stress conditions. Our results highlight the significance of transcriptional reprogramming coupled with improved photosynthetic efficiency in determining salt tolerance in sugarcane.

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Constitutive nitric oxide acting as a possible intercellular signaling molecule in the initiation of radiation-induced DNA double strand breaks in non-irradiated bystander cells

Oncogene ◽

10.1038/sj.onc.1210024 ◽

2006 ◽

Vol 26 (16) ◽

pp. 2330-2339 ◽

Cited By ~ 68

Author(s):

W Han ◽

L Wu ◽

S Chen ◽

L Bao ◽

L Zhang ◽

...

Keyword(s):

Nitric Oxide ◽

Double Strand Breaks ◽

Intercellular Signaling ◽

Dna Double Strand Breaks ◽

Signaling Molecule ◽

Strand Breaks ◽

Radiation Induced ◽

Bystander Cells

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A Simulation Study of the Radiation-Induced Bystander Effect: Modeling with Stochastically Defined Signal Reemission

Computational and Mathematical Methods in Medicine ◽

10.1155/2012/389095 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 7

Author(s):

Kohei Sasaki ◽

Kosuke Wakui ◽

Kaori Tsutsumi ◽

Akio Itoh ◽

Hiroyuki Date

Keyword(s):

Bystander Effect ◽

Spatial Configuration ◽

Signal Transmission ◽

Cell Types ◽

Culture Conditions ◽

Emission Probability ◽

Radiation Induced ◽

Bystander Cells ◽

Radiation Induced Bystander Effect ◽

Cell Culture Conditions

The radiation-induced bystander effect (RIBE) has been experimentally observed for different types of radiation, cell types, and cell culture conditions. However, the behavior of signal transmission between unirradiated and irradiated cells is not well known. In this study, we have developed a new model for RIBE based on the diffusion of soluble factors in cell cultures using a Monte Carlo technique. The model involves the signal emission probability from bystander cells following Poisson statistics. Simulations with this model show that the spatial configuration of the bystander cells agrees well with that of corresponding experiments, where the optimal emission probability is estimated through a large number of simulation runs. It was suggested that the most likely probability falls within 0.63–0.92 for mean number of the emission signals ranging from 1.0 to 2.5.

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DNA Methyltransferases Modulate the Bystander Effect in Mouse Embryonic Stem Cells.

Blood ◽

10.1182/blood.v110.11.4154.4154 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4154-4154

Author(s):

Rebecca E. Rugo ◽

Michael W. Epperly ◽

Darcy Franicola ◽

Benjamin Greenberger ◽

Paavani Komanduri ◽

...

Keyword(s):

Dna Damage ◽

Bystander Effect ◽

Embryonic Stem ◽

Dna Methyltransferases ◽

Epigenetic Mechanisms ◽

Bystander Effects ◽

Strand Breaks ◽

Radiation Induced ◽

Bystander Cells ◽

Gpx Activity

Abstract Cells exposed to radiation or other genotoxic agents can induce DNA damage and other stress responses in non-irradiated cells that are either cultured with the irradiated cells or have been exposed to culture medium from irradiated cells. This is called the bystander effect. In a previous study we found that the descendents of bystander cells exposed to Mitomycin C (MMC) are themselves capable of inducing homologous recombination in un-exposed cells. This suggests that MMC induces persistent and transmissible changes in expression in bystander cells. Bystander effects are likely caused by epigenetic mechanisms rather than “classic” mutations, i.e. changes in DNA sequence. One of the epigenetic mechanisms cells employ for changing expression is DNA methylation in which DNA methyltransferases (DNMTs) add a methyl group to the 5 carbon of cytosine. In this study we asked if ionizing radiation can induce transmissible DNA damage in bystander cells by examining if bystander cells exposed to irradiated cells were themselves able to induce damage in naive cells. Furthermore, we asked if this was dependent on DNMT activity in the irradiated cells. We irradiated wild-type (WT) and DNMT triple knockout (DNMT TKO) mouse embryonic stem cells (ESCs) and after two weeks of continuous culture, we collected conditioned medium (CM). CM was then added to cultures of naive WT ESCs (primary bystanders). Three weeks later, CM was collected from the primary bystanders and added to naïve WT cells (secondary bystanders). We assessed DNA damage by evaluating strand breaks using the alkaline Comet assay and sister chromatid exchange (SCE) analysis. As expected, we found that medium from cells irradiated with 5 Gy induced modest damage in bystander cells. The median Olive tail moment was 2.8 in bystander cells exposed to conditioned medium from irradiated cells compared to 1.0 in control bystander cells (p < 0.0001). Homologous recombination was 0.15 chromatid exchanges per chromosome compared to 0.092 in control bystanders (p < 0.0001). We also observed an increase in strand breaks in secondary bystanders of a similar magnitude to that found in primary bystanders, indicating that radiation-induced bystanders are themselves able to induce damage. In contrast to WT cells, the irradiated DNMT TKO cells did not induce strand breaks in bystander cells, as measured by the Comet assay, but did induce HR. Surprisingly, we also observed that un-irradiated DNMT TKO cells induce DNA damage in bystanders, and furthermore that the magnitude of the effect is similar to that induced by irradiated WT cells. These data suggest that methyltransferases have a complex role in bystander effects. Bystander effects may be mediated by free radicals. To see if the DNMT TKO cells had changes in antioxidant levels, glutathione (GSH) and glutathione peroxidase (GPX) activity were determined. There was no significant change in GSH levels between WT and DNMT TKO cells. However, DNMT TKO cells had significantly higher levels of GPX activity (275.4 + 19.8 mU/mg protein) compared to control cells (122.0 + 16.4 mU/mg, p= 0.0001). Taken together, these results show that radiation-induced bystander cells can themselves induce damage in un-irradiated cells and suggest that cells lacking DNA methylation activity can induce bystander effects.

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The Roles of HIF-1α in Radiosensitivity and Radiation-Induced Bystander Effects Under Hypoxia

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.637454 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jianghong Zhang ◽

Yuhong Zhang ◽

Fang Mo ◽

Gaurang Patel ◽

Karl Butterworth ◽

...

Keyword(s):

Conditioned Medium ◽

Tumor Cells ◽

Target Genes ◽

Human Tumor ◽

Bystander Effects ◽

Glucose Transporter 1 ◽

Hypoxic Conditions ◽

Radiation Induced ◽

Hypoxic Tumor ◽

Bystander Cells

Radiation-induced bystander effects (RIBE) may have potential implications for radiotherapy, yet the radiobiological impact and underlying mechanisms in hypoxic tumor cells remain to be determined. Using two human tumor cell lines, hepatoma HepG2 cells and glioblastoma T98G cells, the present study found that under both normoxic and hypoxic conditions, increased micronucleus formation and decreased cell survival were observed in non-irradiated bystander cells which had been co-cultured with X-irradiated cells or treated with conditioned-medium harvested from X-irradiated cells. Although the radiosensitivity of hypoxic tumor cells was lower than that of aerobic cells, the yield of micronucleus induced in bystander cells under hypoxia was similar to that measured under normoxia indicating that RIBE is a more significant factor in overall radiation damage of hypoxic cells. When hypoxic cells were treated with dimethyl sulfoxide (DMSO), a scavenger of reactive oxygen species (ROS), or aminoguanidine (AG), an inhibitor of nitric oxide synthase (NOS), before and during irradiation, the bystander response was partly diminished. Furthermore, when only hypoxic bystander cells were pretreated with siRNA hypoxia-inducible factor-1α (HIF-1α), RIBE were decreased slightly but if irradiated cells were treated with siRNA HIF-1α, hypoxic RIBE decreased significantly. In addition, the expression of HIF-1α could be increased in association with other downstream effector molecules such as glucose transporter 1 (GLUT-1), vascular endothelial growth factor (VEGF), and carbonic anhydrase (CA9) in irradiated hypoxic cells. However, the expression of HIF-1α expression in bystander cells was decreased by a conditioned medium from isogenic irradiated cells. The current results showed that under hypoxic conditions, irradiated HepG2 and T98G cells showed reduced radiosensitivity by increasing the expression of HIF-1α and induced a syngeneic bystander effect by decreasing the expression of HIF-1α and regulating its downstream target genes in both the irradiated or bystander cells.

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Changes of PTEN gene expression in radiation-induced bystander cells

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2009.00137 ◽

2009 ◽

Vol 29 (2) ◽

pp. 137-141

Author(s):

Jian YANG ◽

Ling HAN ◽

Xian GAO

Keyword(s):

Gene Expression ◽

Pten Gene ◽

Radiation Induced ◽

Bystander Cells

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Induction of autophagy and interleukin 6 secretion in bystander cells: metabolic cooperation for radiation-induced rescue effect?

Journal of Radiation Research ◽

10.1093/jrr/rrx101 ◽

2018 ◽

Vol 59 (2) ◽

pp. 129-140 ◽

Cited By ~ 10

Author(s):

Eva Yi Kong ◽

Shuk Han Cheng ◽

Kwan Ngok Yu

Keyword(s):

Interleukin 6 ◽

Metabolic Cooperation ◽

Rescue Effect ◽

Radiation Induced ◽

Bystander Cells

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Mechanism of protection of bystander cells by exogenous carbon monoxide: Impaired response to damage signal of radiation-induced bystander effect

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis ◽

10.1016/j.mrfmmm.2011.02.011 ◽

2011 ◽

Vol 709-710 ◽

pp. 1-6 ◽

Cited By ~ 15

Author(s):

W. Han ◽

K.N. Yu ◽

L.J. Wu ◽

Y.C. Wu ◽

H.Z. Wang

Keyword(s):

Carbon Monoxide ◽

Bystander Effect ◽

Radiation Induced ◽

Bystander Cells ◽

Radiation Induced Bystander Effect

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Role of ATM in Oxidative Stress-mediated c-Jun Phosphorylation in Response to Ionizing Radiation and CdCl2

Journal of Biological Chemistry ◽

10.1074/jbc.m004517200 ◽

2001 ◽

Vol 276 (15) ◽

pp. 11783-11790 ◽

Cited By ~ 47

Author(s):

Sung A. Lee ◽

Anatoly Dritschilo ◽

Mira Jung

Keyword(s):

Oxidative Stress ◽

Ionizing Radiation ◽

Heme Oxygenase ◽

Redox Homeostasis ◽

Heme Oxygenase 1 ◽

Second Phase ◽

Radiation Induced ◽

Factor C ◽

And Control

Ionizing radiation-induced phosphorylation of the transcription factor c-Jun is impaired in cells derived from individuals with ataxia telangiectasia (AT), in which theATMgene is mutated. We demonstrate here that ATM modulates c-Jun phosphorylation following exposure to ionizing radiation as well as treatment with CdCl2, a potent pro-oxidant. Exposure of AT and control fibroblasts to CdCl2induced a biphasic increase in c-Jun phosphorylation on serine residues 63 and 73, with the extent of the second phase being markedly greater in AT cells than in control cells. Heme oxygenase-1, a marker of oxidative stress, was also significantly induced in AT fibroblasts. Expression of recombinant ATM in AT fibroblasts, however, reduced the extent of the effects of CdCl2on both c-Jun phosphorylation and heme oxygenase-1 induction. Our data suggest that ATM contributes to oxidative stress-mediated signaling that leads to c-Jun phosphorylation by acting as a sensor of ionizing radiation-induced oxidative stress and by modulating intracellular redox homeostasis.

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