Radiation induces IRAK1 expression to promote radioresistance by suppressing autophagic cell death via decreasing the ubiquitination of PRDX1 in glioma cells

by Selleckchem | Jun 06 2023

Radiotherapy is the standard adjuvant treatment for glioma patients; however, the efficacy is limited by radioresistance. The function of Interleukin-1 receptor associated kinase 1 (IRAK1) in tumorigenesis and radioresistance remains to be elucidated. IRAK1 expression and its correlation with prognosis were analyzed in glioma tissues. We found that glioma patients with overexpressed IRAK1 show a poor prognosis. Notably, ionizing radiation (IR) remarkably induces IRAK1 expression, which was decreased by STING antagonist H-151 treatment. JASPAR prediction, ChIP assays, and dual luciferase reporter assays indicated that transcription factor FOXA2, suppressed by STING inhibition, directly binds to the IRAK1 promoter region and activates its transcription. IRAK1 knockdown inhibits malignancy and enhances the radiosensitivity of glioma in vitro and in vivo. To explore the potential IRAK1 interacting targets mediating the radioresistance of glioma cells, IP/Co-IP, LC-MS/MS, GST pull-down, and ubiquitination analyses were conducted. Mechanistically, IRAK1 bound to PRDX1, a major member of antioxidant enzymes, and further prevents ubiquitination and degradation of PRDX1 mediated by E3 ubiquitin ligase HECTD3; Both the DOC and HECT domains of HECTD3 directly interacted with PRDX1 protein. Overexpression of PRDX1 reverses the radiotherapy sensitization effect of IRAK1 depletion by diminishing autophagic cell death. These results suggest the IRAK1-PRDX1 axis provides a potential therapeutic target for glioma patients.

Comments：

The above passage discusses the role of Interleukin-1 receptor associated kinase 1 (IRAK1) in the tumorigenesis and radioresistance of glioma. The study found that glioma patients with overexpressed IRAK1 had a poor prognosis. The study also showed that ionizing radiation (IR) increased IRAK1 expression, which was decreased by STING antagonist H-151 treatment. The transcription factor FOXA2 was found to directly bind to the IRAK1 promoter region and activate its transcription. IRAK1 knockdown was shown to inhibit malignancy and enhance the radiosensitivity of glioma both in vitro and in vivo.

The study also investigated potential IRAK1 interacting targets mediating the radioresistance of glioma cells. It was found that IRAK1 bound to PRDX1, a major member of antioxidant enzymes, and prevented ubiquitination and degradation of PRDX1 mediated by E3 ubiquitin ligase HECTD3. Both the DOC and HECT domains of HECTD3 directly interacted with PRDX1 protein. Overexpression of PRDX1 reversed the radiotherapy sensitization effect of IRAK1 depletion by diminishing autophagic cell death.

Overall, the study suggests that the IRAK1-PRDX1 axis provides a potential therapeutic target for glioma patients, as IRAK1 knockdown could inhibit malignancy and enhance radiosensitivity.