Gene expression profile changes correlating with radioresistance in human cell lines

Ishikawa, Ken-ichi; Koyama-Saegusa, Kumiko; Otsuka, Yoshimi; Ishikawa, Atsuko; Kawai, S; Yasuda, Kaori; Suga, Tomo; Michikawa, Yuichi; Suzuki, Masao; Iwakawa, Mayumi; Imai, Takashi

doi:10.1016/j.ijrobp.2005.12.048

Cited by 22 publications

(15 citation statements)

References 46 publications

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“…In contrast, increase in of PGC1α (p < 0.05) was observed in glioblastoma cells KNS60. Given the direct link of p53 activation necessary for repression for p53-induced PGC1α and PGC1β, this differential observation made in our study could be related to different p53 status in ONS76 (wild type p53) and KNS60 (mutant p53) cells [ 33 – 35 ].…”

Section: Resultsmentioning

confidence: 89%

Targeting DNA-PKcs and telomerase in brain tumour cells

et al. 2014

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BackgroundPatients suffering from brain tumours such as glioblastoma and medulloblastoma have poor prognosis with a median survival of less than a year. Identifying alternative molecular targets would enable us to develop different therapeutic strategies for better management of these tumours.MethodsGlioblastoma (MO59K and KNS60) and medulloblastoma cells (ONS76) were used in this study. Telomerase inhibitory effects of MST-312, a chemically modified-derivative of epigallocatechin gallate, in the cells were assessed using telomere repeat amplification protocol. Gene expression analysis following MST-312 treatment was done by microarray. Telomere length was measured by telomere restriction fragments analysis. Effects of MST-312 on DNA integrity were evaluated by single cell gel electrophoresis, immunofluorescence assay and cytogenetic analysis. Phosphorylation status of DNA-PKcs was measured with immunoblotting and effects on cell proliferation were monitored with cell titre glow and trypan blue exclusion following dual inhibition.ResultsMST-312 showed strong binding affinity to DNA and displayed reversible telomerase inhibitory effects in brain tumour cells. In addition to the disruption of telomere length maintenance, MST-312 treatment decreased brain tumour cell viability, induced cell cycle arrest and double strand breaks (DSBs). DNA-PKcs activation was observed in telomerase-inhibited cells presumably as a response to DNA damage. Impaired DNA-PKcs in MO59J cells or in MO59K cells treated with DNA-PKcs inhibitor, NU7026, caused a delay in the repair of DSBs. In contrast, MST-312 did not induce DSBs in telomerase negative osteosarcoma cells (U2OS). Combined inhibition of DNA-PKcs and telomerase resulted in an increase in telomere signal-free chromosomal ends in brain tumour cells as well. Interestingly, continual exposure of brain tumour cells to telomerase inhibitor led to population of cells, which displayed resistance to telomerase inhibition-mediated cell arrest. DNA-PKcs ablation in these cells, however, confers higher cell sensitivity to telomerase inhibition, inducing cell death.ConclusionsEfficient telomerase inhibition was achieved with acute exposure to MST-312 and this resulted in subtle but significant increase in DSBs. Activation of DNA-PKcs might indicate the requirement of NHEJ pathway in the repair telomerase inhibitor induced DNA damage. Therefore, our results suggest a potential strategy in combating brain tumour cells with dual inhibition of telomerase and NHEJ pathway.

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Section: Resultsmentioning

confidence: 89%

Targeting DNA-PKcs and telomerase in brain tumour cells

et al. 2014

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“…Previously published gene expression profiles of radiation (1 Gy)‐induced mammary carcinomas ( n = 4) were analyzed in parallel . The advanced analysis tool of the Rosetta Resolver Gene Expression Data Analysis System version 4.0 (Rosetta Biosoftware, Seattle, WA) was used as described for integration of the microarray data, using an error modeling approach followed by exclusion of data without statistically significant reliability ( p < 0.001; ∼4,000 were excluded in each case) and identification of differentially expressed genes by one‐way analysis of variance (ANOVA). The microarray data have been deposited in the Gene Expression Omnibus database, http://www.ncbi.nlm.nih.gov/geo/ (accession number, GSE44786).…”

Section: Methodsmentioning

confidence: 99%

Molecular characterization of cancer reveals interactions between ionizing radiation and chemicals on rat mammary carcinogenesis

Imaoka

Nishimura²,

Doi³

et al. 2013

Intl Journal of Cancer

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Although various mechanisms have been inferred for combinatorial actions of multiple carcinogens, these mechanisms have not been well demonstrated in experimental carcinogenesis models. We evaluated mammary carcinogenesis initiated by combined exposure to various doses of radiation and chemical carcinogens. Female rats at 7 weeks of age were c-irradiated (0.2-2 Gy) and/or exposed to 1-methyl-1-nitrosourea (MNU) (20 or 40 mg/kg, single intraperitoneal injection) or 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) (40 mg/kg/day by gavage for 10 days) and were observed until 50 weeks of age. The incidence of mammary carcinoma increased steadily as a function of radiation dose in the absence of chemicals; mathematical analysis supported an additive increase when radiation was combined with a chemical carcinogen, irrespective of the chemical species and its dose. Hras mutations were characteristic of carcinomas that developed after chemical carcinogen treatments and were overrepresented in carcinomas induced by the combination of radiation and MNU (but not PhIP), indicating an interaction of radiation and MNU at the level of initiation. The expression profiles of seven classifier genes, previously shown to distinguish two classes of rat mammary carcinomas, categorized almost all examined carcinomas that developed after individual or combined treatments with radiation (1 Gy) and chemicals as belonging to a single class; more comprehensive screening using microarrays and a separate test sample set failed to identify differences in gene expression profiles among these carcinomas. These results suggest that a complex, multilevel interaction underlies the combinatorial action of radiation and chemical carcinogens in the experimental model.

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“…Microarray is the most comprehensive approach to measure gene expression and has led to outstanding advances in knowledge of radioresistance [8], [9]. However, microarray has several limitations such as probe hybridization kinetics, probe selection (need to know genomic loci and features), background hybridization and cross-platform comparability [10].…”

Section: Introductionmentioning

confidence: 99%

Investigation of Radiation-induced Transcriptome Profile of Radioresistant Non-small Cell Lung Cancer A549 Cells Using RNA-seq

et al. 2013

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Radioresistance is a main impediment to effective radiotherapy for non-small cell lung cancer (NSCLC). Despite several experimental and clinical studies of resistance to radiation, the precise mechanism of radioresistance in NSCLC cells and tissues still remains unclear. This result could be explained by limitation of previous researches such as a partial understanding of the cellular radioresistance mechanism at a single molecule level. In this study, we aimed to investigate extensive radiation responses in radioresistant NSCLC cells and to identify radioresistance-associating factors. For the first time, using RNA-seq, a massive sequencing-based approach, we examined whole-transcriptome alteration in radioresistant NSCLC A549 cells under irradiation, and verified significant radiation-altered genes and their chromosome distribution patterns. Also, bioinformatic approaches (GO analysis and IPA) were performed to characterize the radiation responses in radioresistant A549 cells. We found that epithelial–mesenchymal transition (EMT), migration and inflammatory processes could be meaningfully related to regulation of radiation responses in radioresistant A549 cells. Based on the results of bioinformatic analysis for the radiation-induced transcriptome alteration, we selected seven significant radiation-altered genes (SESN2, FN1, TRAF4, CDKN1A, COX-2, DDB2 and FDXR) and then compared radiation effects in two types of NSCLC cells with different radiosensitivity (radioresistant A549 cells and radiosensitive NCI-H460 cells). Interestingly, under irradiation, COX-2 showed the most significant difference in mRNA and protein expression between A549 and NCI-H460 cells. IR-induced increase of COX-2 expression was appeared only in radioresistant A549 cells. Collectively, we suggest that COX-2 (also known as prostaglandin-endoperoxide synthase 2 (PTGS2)) could have possibility as a putative biomarker for radioresistance in NSCLC cells.

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Gene expression profile changes correlating with radioresistance in human cell lines

Cited by 22 publications

References 46 publications

Targeting DNA-PKcs and telomerase in brain tumour cells

Targeting DNA-PKcs and telomerase in brain tumour cells

Molecular characterization of cancer reveals interactions between ionizing radiation and chemicals on rat mammary carcinogenesis

Investigation of Radiation-induced Transcriptome Profile of Radioresistant Non-small Cell Lung Cancer A549 Cells Using RNA-seq

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