| Increased radioresistance via G12S K-Ras by compensatory upregulation of MAPK and PI3K pathways in epithelial cancer. | |
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MedLine Citation:
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PMID: 22302684 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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BACKGROUND: Irradiation-induced signaling via the 2 pathways, Raf-MEK-ERK and PI3K-Akt, is known to be closely associated with a limited response to radiotherapy. In the present study we analyzed the relevance of constitutively active K-Ras for postradiogenic pathway stimulation and the option of coordinated inhibition to overcome these rescue mechanisms. METHODS: We used 2 epithelial tumor cell lines as a model system, one of them harboring a G12S K-Ras mutation. Cells were irradiated and the effect of combined treatment with ionizing radiation and inhibitors on the expression of pERK and pAkt was determined by Western blotting. Additionally, clonogenic assays were performed to functionally analyze survival of the cell lines. RESULTS: Compared with the nonmutated cells we observed the G12S cell line showing a clearly reduced response to inhibitor treatment under irradiation. In the case of pharmacologic inhibition of 1 of the pathways a compensatory upregulation of the second cascade leading to increased clonogenic survival seems feasible. However, there was a good functional response of this cell line to double inhibition with both compounds represented by minimized colony forming ability. The activation of ERK and Akt after irradiation was confirmed in xenotransplants showing elevated postradiogenic protein levels. CONCLUSION: With our data we confirmed our hypothesis of postradiogenic constitutive activation of the 2 pathways both required for Ras-mediated radioresistance in epithelial cells. If this effect should prove itself as a general mechanism in Ras-mutated tumors, application of specific inhibitors to block both cascades in parallel could contribute to enhance radiosensitivity in these types of cancer. © 2012 Wiley Periodicals, Inc. Head Neck, 2012. |
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Authors:
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Annette Affolter; Martynas Drigotas; Kai Fruth; Irene Schmidtmann; Christoph Brochhausen; Wolf J Mann; Jürgen Brieger |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-2-2 |
Journal Detail:
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Title: Head & neck Volume: - ISSN: 1097-0347 ISO Abbreviation: - Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-2-3 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8902541 Medline TA: Head Neck Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 Wiley Periodicals, Inc. |
Affiliation:
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Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University, Mainz, Germany. affolter@hno.klinik.uni-mainz.de. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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