Enhanced radiosensitivity by 6-thio-dG via increasing telomere dysfunction and ataxia telangiectasia mutated inhibition in non-small cell lung cancer
Objective: To investigate the radiosensitivity of 6-thio-dG and its underlying molecular mechanisms in non-small cell lung cancer (NSCLC). Methods: H1299 and A549 NSCLC cells were pretreated with 6-thio-dG for one week and then exposed to γ-irradiation. Cell proliferation and survival were quantifie...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | Radiation Medicine and Protection |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666555722000235 |
| _version_ | 1797712101391728640 |
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| author | Nan Wei Qian Li Shaopeng Chen Shengmin Xu Lijun Wu |
| author_facet | Nan Wei Qian Li Shaopeng Chen Shengmin Xu Lijun Wu |
| author_sort | Nan Wei |
| collection | DOAJ |
| description | Objective: To investigate the radiosensitivity of 6-thio-dG and its underlying molecular mechanisms in non-small cell lung cancer (NSCLC). Methods: H1299 and A549 NSCLC cells were pretreated with 6-thio-dG for one week and then exposed to γ-irradiation. Cell proliferation and survival were quantified using clonogenic assays. DNA damage was assessed using immunofluorescence for γH2AX. Telomere dysfunction-induced foci analysis was performed by the co-localization of telomere signals (FISH) and γH2AX. Telomere fusion was defined as two telomere signals merged into one at the chromosome by immuno-FISH in metaphase spreads. Proteins related to the DNA damage response were detected using Western blot analysis. Apoptosis wasanalyzed using flow cytometry and Western blot. Results: The presence of 6-thio-dG increased the radio sensitivity of H1299 and A549 cells (P<0.05), but had no effect on the normal human lung fibroblast line, MRC5. 6-thio-dG pretreatment significantly reduced the clonogenic potential induced by γ-ray irradiation and aggravated genomic DNA and telomeric DNA damage (P<0.05). In addition, 6-thio-dG pretreatment effectively increased γ-ray irradiation induced telomere dysfunction (P<0.05), resulting in disruption of chromosome stability and inhibition of the ATM pathway, thereby impairing genomic DNA and telomeric DNA repair, which was closely associated with enhanced drug-mediated radiation-induced apoptosis. Conclusions: 6-thio-dG increases the radiosensitivity of NSCLC by inhibiting ATM and inducing telomere dysfunction, which can potentially be used as a strategy for radiotherapy for NSCLC. |
| first_indexed | 2024-03-12T07:16:49Z |
| format | Article |
| id | doaj.art-0b85c8fb385047d798a738ad49b77818 |
| institution | Directory Open Access Journal |
| issn | 2666-5557 |
| language | English |
| last_indexed | 2024-03-12T07:16:49Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Radiation Medicine and Protection |
| spelling | doaj.art-0b85c8fb385047d798a738ad49b778182023-09-02T22:43:58ZengElsevierRadiation Medicine and Protection2666-55572022-06-01326471Enhanced radiosensitivity by 6-thio-dG via increasing telomere dysfunction and ataxia telangiectasia mutated inhibition in non-small cell lung cancerNan Wei0Qian Li1Shaopeng Chen2Shengmin Xu3Lijun Wu4Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; University of Science and Technology of China, Hefei 230026, ChinaHefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; University of Science and Technology of China, Hefei 230026, ChinaHefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, ChinaInstitutes of Physical Science and Information Technology, Anhui University, Hefei 230601, China; Corresponding author.Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; University of Science and Technology of China, Hefei 230026, China; Institutes of Physical Science and Information Technology, Anhui University, Hefei 230601, China; Corresponding author.Objective: To investigate the radiosensitivity of 6-thio-dG and its underlying molecular mechanisms in non-small cell lung cancer (NSCLC). Methods: H1299 and A549 NSCLC cells were pretreated with 6-thio-dG for one week and then exposed to γ-irradiation. Cell proliferation and survival were quantified using clonogenic assays. DNA damage was assessed using immunofluorescence for γH2AX. Telomere dysfunction-induced foci analysis was performed by the co-localization of telomere signals (FISH) and γH2AX. Telomere fusion was defined as two telomere signals merged into one at the chromosome by immuno-FISH in metaphase spreads. Proteins related to the DNA damage response were detected using Western blot analysis. Apoptosis wasanalyzed using flow cytometry and Western blot. Results: The presence of 6-thio-dG increased the radio sensitivity of H1299 and A549 cells (P<0.05), but had no effect on the normal human lung fibroblast line, MRC5. 6-thio-dG pretreatment significantly reduced the clonogenic potential induced by γ-ray irradiation and aggravated genomic DNA and telomeric DNA damage (P<0.05). In addition, 6-thio-dG pretreatment effectively increased γ-ray irradiation induced telomere dysfunction (P<0.05), resulting in disruption of chromosome stability and inhibition of the ATM pathway, thereby impairing genomic DNA and telomeric DNA repair, which was closely associated with enhanced drug-mediated radiation-induced apoptosis. Conclusions: 6-thio-dG increases the radiosensitivity of NSCLC by inhibiting ATM and inducing telomere dysfunction, which can potentially be used as a strategy for radiotherapy for NSCLC.http://www.sciencedirect.com/science/article/pii/S2666555722000235Non-small cell lung cancerRadiosensitivity6-thio-dGTelomeric DNA damageApoptosis |
| spellingShingle | Nan Wei Qian Li Shaopeng Chen Shengmin Xu Lijun Wu Enhanced radiosensitivity by 6-thio-dG via increasing telomere dysfunction and ataxia telangiectasia mutated inhibition in non-small cell lung cancer Radiation Medicine and Protection Non-small cell lung cancer Radiosensitivity 6-thio-dG Telomeric DNA damage Apoptosis |
| title | Enhanced radiosensitivity by 6-thio-dG via increasing telomere dysfunction and ataxia telangiectasia mutated inhibition in non-small cell lung cancer |
| title_full | Enhanced radiosensitivity by 6-thio-dG via increasing telomere dysfunction and ataxia telangiectasia mutated inhibition in non-small cell lung cancer |
| title_fullStr | Enhanced radiosensitivity by 6-thio-dG via increasing telomere dysfunction and ataxia telangiectasia mutated inhibition in non-small cell lung cancer |
| title_full_unstemmed | Enhanced radiosensitivity by 6-thio-dG via increasing telomere dysfunction and ataxia telangiectasia mutated inhibition in non-small cell lung cancer |
| title_short | Enhanced radiosensitivity by 6-thio-dG via increasing telomere dysfunction and ataxia telangiectasia mutated inhibition in non-small cell lung cancer |
| title_sort | enhanced radiosensitivity by 6 thio dg via increasing telomere dysfunction and ataxia telangiectasia mutated inhibition in non small cell lung cancer |
| topic | Non-small cell lung cancer Radiosensitivity 6-thio-dG Telomeric DNA damage Apoptosis |
| url | http://www.sciencedirect.com/science/article/pii/S2666555722000235 |
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