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Radioresistance of Stat1 over-expressing tumour cells is associated with suppressed apoptotic response to cytotoxic agents and increased IL6-IL8 signalling

PURPOSE: To determine the mechanisms of Signal Transducer and Activator of Transcription 1 (Stat1)-associated radioresistance developed by nu61 tumour selected in vivo by fractionated irradiation of the parental radiosensitive tumour SCC61. MATERIALS AND METHODS: Radioresistence of nu61 and SCC61 in...

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Autores principales: Efimova, Elena V., Liang, Hua, Pitroda, Sean P., Labay, Edwardine, Darga, Thomas E., Levina, Vera, Lokshin, Anna, Roizman, Bernard, Weichselbaum, Ralph R., Khodarev, Nikolai N.
Formato: Texto
Lenguaje:English
Publicado: Informa Healthcare 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690884/
https://www.ncbi.nlm.nih.gov/pubmed/19437244
http://dx.doi.org/10.1080/09553000902838566
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author Efimova, Elena V.
Liang, Hua
Pitroda, Sean P.
Labay, Edwardine
Darga, Thomas E.
Levina, Vera
Lokshin, Anna
Roizman, Bernard
Weichselbaum, Ralph R.
Khodarev, Nikolai N.
author_facet Efimova, Elena V.
Liang, Hua
Pitroda, Sean P.
Labay, Edwardine
Darga, Thomas E.
Levina, Vera
Lokshin, Anna
Roizman, Bernard
Weichselbaum, Ralph R.
Khodarev, Nikolai N.
author_sort Efimova, Elena V.
collection PubMed
description PURPOSE: To determine the mechanisms of Signal Transducer and Activator of Transcription 1 (Stat1)-associated radioresistance developed by nu61 tumour selected in vivo by fractionated irradiation of the parental radiosensitive tumour SCC61. MATERIALS AND METHODS: Radioresistence of nu61 and SCC61 in vitro was measured by clonogenic assay. Apoptotic response of nu61 and SCC61 cells to genotoxic stress was examined using caspase-based apoptotic assays. Co-cultivation of carboxyfluorescein diacetate, succinimidyl ester (CFDE-SE)-labeled nu61 with un-labeled SCC61 was performed at 1:1 ratio. Production of interleukin-6, interleukin-8 and soluble receptor of interleukin 6 (IL6, IL8 and sIL6R) was measured using Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: Radioresistant nu61 was also resistant to interferon-gamma (IFNγ) and the death ligands of tumour necrosis factor alpha receptor (TNFR) family when compared to SCC61. This combined resistance is due to an impaired apoptotic response in nu61. Relative to SCC61, nu61 produced more IL6, IL8 and sIL6R. Using Stat1 knock-downs we demonstrated that IL6 and IL8 production is Stat1-dependent. Treatment with neutralising antibodies to IL6 and IL8, but not to either cytokine alone sensitised nu61 to genotoxic stress induced apoptosis. CONCLUSION: Nu61, which over-expresses Stat1 pathway, is deficient in apoptotic response to ionising radiation and cytotoxic ligands. This resistance to apoptosis is associated with Stat1-dependent production of IL6 and IL8 and suppression of 8, 9 and 3.
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spelling pubmed-26908842009-06-04 Radioresistance of Stat1 over-expressing tumour cells is associated with suppressed apoptotic response to cytotoxic agents and increased IL6-IL8 signalling Efimova, Elena V. Liang, Hua Pitroda, Sean P. Labay, Edwardine Darga, Thomas E. Levina, Vera Lokshin, Anna Roizman, Bernard Weichselbaum, Ralph R. Khodarev, Nikolai N. Int J Radiat Biol Article PURPOSE: To determine the mechanisms of Signal Transducer and Activator of Transcription 1 (Stat1)-associated radioresistance developed by nu61 tumour selected in vivo by fractionated irradiation of the parental radiosensitive tumour SCC61. MATERIALS AND METHODS: Radioresistence of nu61 and SCC61 in vitro was measured by clonogenic assay. Apoptotic response of nu61 and SCC61 cells to genotoxic stress was examined using caspase-based apoptotic assays. Co-cultivation of carboxyfluorescein diacetate, succinimidyl ester (CFDE-SE)-labeled nu61 with un-labeled SCC61 was performed at 1:1 ratio. Production of interleukin-6, interleukin-8 and soluble receptor of interleukin 6 (IL6, IL8 and sIL6R) was measured using Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: Radioresistant nu61 was also resistant to interferon-gamma (IFNγ) and the death ligands of tumour necrosis factor alpha receptor (TNFR) family when compared to SCC61. This combined resistance is due to an impaired apoptotic response in nu61. Relative to SCC61, nu61 produced more IL6, IL8 and sIL6R. Using Stat1 knock-downs we demonstrated that IL6 and IL8 production is Stat1-dependent. Treatment with neutralising antibodies to IL6 and IL8, but not to either cytokine alone sensitised nu61 to genotoxic stress induced apoptosis. CONCLUSION: Nu61, which over-expresses Stat1 pathway, is deficient in apoptotic response to ionising radiation and cytotoxic ligands. This resistance to apoptosis is associated with Stat1-dependent production of IL6 and IL8 and suppression of 8, 9 and 3. Informa Healthcare 2009-05-12 2009-05 /pmc/articles/PMC2690884/ /pubmed/19437244 http://dx.doi.org/10.1080/09553000902838566 Text en © 2009 Informa Healthcare USA, Inc. http://creativecommons.org/licenses/by/2.0/ This is an open access article distributed under the Supplemental Terms and Conditions for iOpenAccess articles published in Informa Healthcare journals (http://www.informaworld.com/mpp/uploads/iopenaccess_tcs.pdf) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
Efimova, Elena V.
Liang, Hua
Pitroda, Sean P.
Labay, Edwardine
Darga, Thomas E.
Levina, Vera
Lokshin, Anna
Roizman, Bernard
Weichselbaum, Ralph R.
Khodarev, Nikolai N.
Radioresistance of Stat1 over-expressing tumour cells is associated with suppressed apoptotic response to cytotoxic agents and increased IL6-IL8 signalling
title Radioresistance of Stat1 over-expressing tumour cells is associated with suppressed apoptotic response to cytotoxic agents and increased IL6-IL8 signalling
title_full Radioresistance of Stat1 over-expressing tumour cells is associated with suppressed apoptotic response to cytotoxic agents and increased IL6-IL8 signalling
title_fullStr Radioresistance of Stat1 over-expressing tumour cells is associated with suppressed apoptotic response to cytotoxic agents and increased IL6-IL8 signalling
title_full_unstemmed Radioresistance of Stat1 over-expressing tumour cells is associated with suppressed apoptotic response to cytotoxic agents and increased IL6-IL8 signalling
title_short Radioresistance of Stat1 over-expressing tumour cells is associated with suppressed apoptotic response to cytotoxic agents and increased IL6-IL8 signalling
title_sort radioresistance of stat1 over-expressing tumour cells is associated with suppressed apoptotic response to cytotoxic agents and increased il6-il8 signalling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690884/
https://www.ncbi.nlm.nih.gov/pubmed/19437244
http://dx.doi.org/10.1080/09553000902838566
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