The Influence of the Heat Shock Response on Radioresistance

• Applicant: Professorin Dr. Gabriele Multhoff, since 6/2019
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 345848773

Ionizing irradiation is an important therapeutic modality for patients with solid tumors. Due to the normal tissue toxicity, the radiation dose that can be administered is limited and not always sufficient for tumor control. Therefore, the development of novel therapeutic approaches that improve radiosensitivity in resistant tumor cells is urgently required.Heat shock protein 90 (Hsp90) stabilizes many different oncogenic client proteins that are important for tumor cell survival and thus Hsp90 contributes to radioresistance of tumor cells. Inhibition of Hsp90 is considered as a promising concept to improve radiosensitivity. However, their efficacy is limited due to activation of the transcription factor HSF1 (heat shock factor 1) which in turn induces the transcription of the proapoptotic heat shock proteins Hsp27 and Hsp70.We could show that HSF1 knockdown enhances the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in the lung cancer cell line H1339. In contrast, HSF1 knockdown does not increase radiosensitivity after Hsp90 inhibition in EPLC-272H lung cancer cells. We assume that the difference between these two cell lines could be due to the differential expression and regulation of Hsp27.In this proposal, we want to clarify the mechanisms that are responsible for the differences in radiosensitization and analyze the roles of Hsp27 and Hsp70 in regard to radioresistance.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Dr. Annett Kühnel, until 5/2019