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Heat shock protein 90-sheltered overexpression of insulin-like growth factor 1 receptor contributes to malignancy of thymic epithelial tumors

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Purpose: The underlying molecular mechanisms of thymic epithelial malignancies (TEMs) are poorly understood. Consequently, there is a lack of efficacious targeted therapies and patient prognosis remains dismal, particularly for advanced TEMs. We sought to investigate protumorigenic mechanism relevan...

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Main Authors: Breinig, Marco (Author) , Mayer, Philipp (Author) , Harjung, Andreas (Author) , Goeppert, Benjamin (Author) , Malz, Mona (Author) , Penzel, Roland (Author) , Neumann, Olaf (Author) , Hartmann, Arndt (Author) , Dienemann, Hendrik (Author) , Giaccone, Giuseppe (Author) , Schirmacher, Peter (Author) , Kern, Michael A. (Author) , Chiosis, Gabriela (Author) , Rieker, Ralf Joachim (Author)
Format: Article (Journal)
Language:English
Published: April 14 2011
In: Clinical cancer research
Year: 2011, Volume: 17, Issue: 8, Pages: 2237-2249
ISSN:1557-3265
DOI:10.1158/1078-0432.CCR-10-1689
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/1078-0432.CCR-10-1689
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Author Notes:Marco Breinig, Philipp Mayer, Andreas Harjung, Benjamin Goeppert, Mona Malz, Roland Penzel, Olaf Neumann, Arndt Hartmann, Hendrik Dienemann, Giuseppe Giaccone, Peter Schirmacher, Michael André Kern, Gabriela Chiosis, and Ralf Joachim Rieker
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Summary:Purpose: The underlying molecular mechanisms of thymic epithelial malignancies (TEMs) are poorly understood. Consequently, there is a lack of efficacious targeted therapies and patient prognosis remains dismal, particularly for advanced TEMs. We sought to investigate protumorigenic mechanism relevant to this understudied cancer.Experimental Design: Recently established cell lines derived from thymic epithelial tumors were used as a model system. The antitumor activity of specific heat shock protein 90 (Hsp90) inhibitors was investigated by an analysis of cell viability, cell cycle, and apoptosis using MTT-assays and flow cytometry. Western blotting was used to investigate the altered expression of Hsp90 clients. Pharmacological inhibitors against select Hsp90 clients, as well as RNAi, were employed to test the relevance of each client independently. Tissue microarray analysis was performed to match the in vitro findings with observations obtained from patient-derived samples.Results: Hsp90 inhibition significantly reduces cell viability of thymic carcinoma cells, induces cell cycle arrest and apoptosis, and blocks invasiveness. Hsp90 inhibition triggers the degradation of multiple oncogenic clients, for example insulin-like growth factor 1 receptor (IGF-1R), CDK4, and the inactivation of PI3K/Akt and RAF/Erk signaling. Mechanistically, the IGF/IGF-1R-signaling axis contributes to the establishment of the antiapoptotic phenotype of thymic cancer cells. Finally, IGF-1R is overexpressed in advanced TEMs.Conclusions: We have unraveled a novel protumorigenic mechanism in TEMs, namely Hsp90-capacitated overexpression of IGF-1R, which confers apoptosis evasion in malignant thymic epithelial cells. Our data indicate that Hsp90 inhibition, which simultaneously blocks multiple cancer hallmarks, represents a therapeutic strategy in TEMs that may merit evaluation in clinical trials.
Item Description:Gesehen am 03.06.2022
Physical Description:Online Resource
ISSN:1557-3265
DOI:10.1158/1078-0432.CCR-10-1689

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