An IRAK1-PIN1 Signalling Axis Drives Intrinsic Tumour Resistance to Radiation Therapy
| Autor: | Xiao Zhen Zhou, Richard M. White, Ruth Thompson, Peter Man-Un Ung, Samuel Sidi, Peter H. Liu, John V. Heymach, Richa B. Shah, Julio A. Aguirre-Ghiso, Arshi Arora, Shingo Kozono, Yuanyuan Li, Heath D. Skinner, Robert G. Maki, John M. Barbaro, Vincent Brechin, Avner Schlessinger, Kun Ping Lu, Elisa de Stanchina, Andrej Gorbatenko, Jose M. Silva, Katherine S. Panageas, Renuka Raman |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Mice
SCID Radiation Tolerance Article 03 medical and health sciences 0302 clinical medicine Mice Inbred NOD Cell Line Tumor Neoplasms Prolyl isomerase Animals Humans Zebrafish 030304 developmental biology Mice Knockout 0303 health sciences Chemistry Kinase HEK 293 cells IRAK1 Cell Biology IRAK4 HCT116 Cells Xenograft Model Antitumor Assays 3. Good health Cell biology NIMA-Interacting Peptidylprolyl Isomerase HEK293 Cells Interleukin-1 Receptor-Associated Kinases Apoptosis 030220 oncology & carcinogenesis Mutation PIN1 Cancer research MCF-7 Cells Signal transduction Tumor Suppressor Protein p53 HeLa Cells Signal Transduction |
| Zdroj: | Nature cell biology |
| ISSN: | 1476-4679 1465-7392 |
| Popis: | Drug-based strategies to overcome tumour resistance to radiotherapy (R-RT) remain limited by the single-agent toxicity of traditional radiosensitizers (for example, platinums) and a lack of targeted alternatives. In a screen for compounds that restore radiosensitivity in p53 mutant zebrafish while tolerated in non-irradiated wild-type animals, we identified the benzimidazole anthelmintic oxfendazole. Surprisingly, oxfendazole acts via the inhibition of IRAK1, a kinase thus far implicated in interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR) immune responses. IRAK1 drives R-RT in a pathway involving IRAK4 and TRAF6 but not the IL-1R/TLR-IRAK adaptor MyD88. Rather than stimulating nuclear factor-κB, radiation-activated IRAK1 prevented apoptosis mediated by the PIDDosome complex (comprising PIDD, RAIDD and caspase-2). Countering this pathway with IRAK1 inhibitors suppressed R-RT in tumour models derived from cancers in which TP53 mutations predict R-RT. Moreover, IRAK1 inhibitors synergized with inhibitors of PIN1, a prolyl isomerase essential for IRAK1 activation in response to pathogens and, as shown here, in response to ionizing radiation. These data identify an IRAK1 radiation-response pathway as a rational chemoradiation therapy target. |
| Databáze: | OpenAIRE |
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