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Open AccessArticle

Radiosensitization of HSF-1 Knockdown Lung Cancer Cells by Low Concentrations of Hsp90 Inhibitor NVP-AUY922

1
Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München (TUM), Ismaninger Straße 22, 81675 Munich, Germany
2
Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
3
Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Munich, 81675 Munich, Germany
4
Institute for Medical Informatics, Statistics and Epidemiology, Technische Universität München, Klinikum rechts der Isar, Ismaningerstr. 21, 81675 Munich, Germany
5
Center for Translational Cancer Research, Technische Universität München (TranslaTUM), Klinikum rechts der Isar, Einsteinstr. 25, 81675 Munich, Germany
*
Author to whom correspondence should be addressed.
Shared first authorship.
Cells 2019, 8(10), 1166; https://doi.org/10.3390/cells8101166
Received: 10 September 2019 / Revised: 26 September 2019 / Accepted: 27 September 2019 / Published: 28 September 2019
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
The inhibition of heat shock protein 90 (Hsp90) a molecular chaperone for multiple oncogenic client proteins is considered as a promising approach to overcome radioresistance. Since most Hsp90 inhibitors activate HSF-1 that induces the transcription of cytoprotective and tumor-promoting stress proteins such as Hsp70 and Hsp27, a combined approach consisting of HSF-1 knockdown (k.d.) and Hsp90 inhibition was investigated. A specific HSF-1 k.d. was achieved in H1339 lung cancer cells using RNAi-Ready pSIRENRetroQ vectors with puromycin resistance. The Hsp90 inhibitor NVP-AUY922 was evaluated at low concentrations—ranging from 1–10 nM—in control and HSF-1 k.d. cells. Protein expression (i.e., Hsp27/Hsp70, HSF-1, pHSF-1, Akt, ß-actin) and transcriptional activity was assessed by western blot analysis and luciferase assays and radiosensitivity was measured by proliferation, apoptosis (Annexin V, active caspase 3), clonogenic cell survival, alkaline comet, γH2AX, 53BP1, and Rad51 foci assays. The k.d. of HSF-1 resulted in a significant reduction of basal and NVP-AUY922-induced Hsp70/Hsp27 expression levels. A combined approach consisting of HSF-1 k.d. and low concentrations of the Hsp90 inhibitor NVP-AUY922 reduces the Hsp90 client protein Akt and potentiates radiosensitization, which involves an impaired homologous recombination mediated by Rad51. Our findings are key for clinical applications of Hsp90 inhibitors with respect to adverse hepatotoxic effects. View Full-Text
Keywords: heat shock factor (HSF-1) knockdown; heat shock proteins 70 and 27; radiosensitization; Hsp90 inhibitor NVP-AUY922; homologous recombination (HR) heat shock factor (HSF-1) knockdown; heat shock proteins 70 and 27; radiosensitization; Hsp90 inhibitor NVP-AUY922; homologous recombination (HR)
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MDPI and ACS Style

Kühnel, A.; Schilling, D.; Combs, S.E.; Haller, B.; Schwab, M.; Multhoff, G. Radiosensitization of HSF-1 Knockdown Lung Cancer Cells by Low Concentrations of Hsp90 Inhibitor NVP-AUY922. Cells 2019, 8, 1166.

AMA Style

Kühnel A, Schilling D, Combs SE, Haller B, Schwab M, Multhoff G. Radiosensitization of HSF-1 Knockdown Lung Cancer Cells by Low Concentrations of Hsp90 Inhibitor NVP-AUY922. Cells. 2019; 8(10):1166.

Chicago/Turabian Style

Kühnel, Annett; Schilling, Daniela; Combs, Stephanie E.; Haller, Bernhard; Schwab, Melissa; Multhoff, Gabriele. 2019. "Radiosensitization of HSF-1 Knockdown Lung Cancer Cells by Low Concentrations of Hsp90 Inhibitor NVP-AUY922" Cells 8, no. 10: 1166.

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