Ionizing Radiation-induced Apoptosis in Ataxia-Telangiectasia Fibroblasts

Zhang, Yin; Dimtchev, Alexandre; Dritschilo, Anatoly; Jung, Mira

doi:10.1074/jbc.m010525200

Cited by 23 publications

(2 citation statements)

References 46 publications

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“…In contrast, ATM has been implicated in post-radiation repair [17]. We investigated the role of ATM in radiation-induced phosphorylation of Hsp90α by using cells (AT5BIVA) derived from a patient with mutated ATM [18, 19]. Figure 2A shows that in AT5BIVA-ATM cells that have functional reconstituted ATM, Hsp90α is phosphorylated as early as 1 minute after IR-induced DNA damage, and Hsp90α phosphorylation is correlated with H2AX S139 phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

ATM is the primary kinase responsible for phosphorylation of Hsp90α after ionizing radiation

et al. 2016

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Heat shock protein 90 is a chaperone that plays an essential role in the stabilization of a large number of signal transduction molecules, many of which are associated with oncogenesis. An Hsp90 isoform (Hsp90α) has been shown to be selectively phosphorylated on two N-terminal threonine residues (threonine 5 and 7) and is involved in the DNA damage response and apoptosis. However, the kinase that phosphorylates Hsp90α after ionizing radiation (IR) and its role in post-radiation DNA repair remains unclear. Inasmuch as several proteins of the DNA damage response machinery are Hsp90 clients, the functional consequences of Hsp90α phosphorylation following IR have implications for the design of novel radiosensitizing agents that specifically target the Hsp90α isoform. Here we show that ATM phosphorylates Hsp90α at the T5/7 residues immediately after IR. The kinetics of Hsp90α T5/7 phosphorylation correlate with the kinetics of H2AX S139 phosphorylation (γH2AX). Although Hsp90α is located in both the cytoplasm and nucleus, only nuclear Hsp90α is phosphorylated by ATM after IR. The siRNA mediated knockdown of Hsp90α sensitizes head and neck squamous cell carcinoma cells, lung cancer cells and lung fibroblasts to IR. Furthermore, MEF cells that are Hsp90α null have reduced levels of γH2AX indicating that Hsp90α is important for the formation of γH2AX. Thus, this study provides evidence that Hsp90α is a component of the signal transduction events mediated by ATM following IR, and that Hsp90α loss decreases γH2AX levels. This work supports additional investigation into Hsp90α T5/7 phosphorylation with the goal of developing targeted radiosensitizing therapies.

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Section: Resultsmentioning

confidence: 99%

ATM is the primary kinase responsible for phosphorylation of Hsp90α after ionizing radiation

et al. 2016

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“…Caspases 3 and 9 are also known to be involved in radiation-induced apoptosis [19]. Thus, we used western blotting to confirm the activation levels of caspases 3 and 9 in cells treated with 5-aza-dC and/or IR.…”

Section: Resultsmentioning

confidence: 99%

Combination Effect of Epigenetic Regulation and Ionizing Radiation in Colorectal Cancer Cells

et al. 2014

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Exposure of cells to ionizing radiation (IR) induces, not only, activation of multiple signaling pathways that play critical roles in cell fate determination, but also alteration of molecular pathways involved in cell death or survival. Recently, DNA methylation has been established as a critical epigenetic process involved in the regulation of gene expression in cancer cells, suggesting that DNA methylation inhibition may be an effective cancer treatment strategy. Because alterations of gene expression by DNA methylation have been considered to influence radioresponsiveness, we investigated the effect of a DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5-aza-dC), on radiosensitivity. In addition, we investigated the underlying cellular mechanisms of combination treatments of ionizing irradiation (IR) and 5-aza-dC in human colon cancer cells. Colon cancer cell lines were initially tested for radiation sensitivity by IR in vitro and were treated with two different doses of 5-aza-dC. Survival of these cell lines was measured using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and clonogenic assays. The effects of 5-aza-dC along with irradiation on cell growth, cell cycle distribution, apoptosis, and apoptosis-related gene expression were examined. Combination irradiation treatment with 5-aza-dC significantly decreased growth activity compared with irradiation treatment alone or with 5-aza-dC treatment alone. The percentage of HCT116 cells in the sub-G1 phase and their apoptotic rate was increased when cells were treated with irradiation in combination with 5-aza-dC compared with either treatment alone. These observations were strongly supported by increased caspase activity, increased comet tails using comet assays, and increased protein levels of apoptosis-associated molecules (caspase 3/9, cleaved PARP). Our data demonstrated that 5-aza-dC enhanced radiosensitivity in colon cancer cells, and the combination effects of 5-aza-dC with radiation showed greater cellular effects than that of single treatment, suggesting that the combination of 5-aza-dC and radiation has the potential to become a clinical strategy for the treatment of cancer.

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Rational Design and Development of Radiation-Sensitizing Histone Deacetylase Inhibitors

Jung

Kozikowski

Dritschilo

2005

C&B

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Histone deacetylases (HDACs) offer potentially attractive molecular targets for sensitizing cancers to treatment with radiation therapy. By affecting patterns of gene expression, differentiation, apoptosis, and enhanced responses to therapeutic agents may be induced in cancer cells. Here, we review the drug characteristics underlying design and screening of HDAC inhibitors with a focus on radiation-sensitizing properties. Radiation-sensitizing capacities have been observed in three model systems, squamous carcinoma of head and neck origin (SQ-20B), prostate adenocarcinoma (PC-3), and breast adenocarcinoma (MCF7). Cell-type specificities in radiation-sensitizing properties have been observed. Mechanisms underlying specificity are under investigation.

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Ionizing Radiation-induced Apoptosis in Ataxia-Telangiectasia Fibroblasts

Cited by 23 publications

References 46 publications

ATM is the primary kinase responsible for phosphorylation of Hsp90α after ionizing radiation

ATM is the primary kinase responsible for phosphorylation of Hsp90α after ionizing radiation

Combination Effect of Epigenetic Regulation and Ionizing Radiation in Colorectal Cancer Cells

Rational Design and Development of Radiation-Sensitizing Histone Deacetylase Inhibitors

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