Csnk1a1 inhibition modulates the inflammatory secretome and enhances response to radiotherapy in glioma

Abstract

Glioblastoma multiforme (GBM), a fatal brain tumour with no available targeted therapies, has a poor prognosis. At present, radiotherapy is one of the main methods to treat glioma, but it leads to an obvious increase in inflammatory factors in the tumour microenvironment, especially IL‐6 and CXCL1, which plays a role in tumour to resistance radiotherapy and tumorigenesis. Casein kinase 1 alpha 1 (CK1α) (encoded on chromosome 5q by Csnk1a1) is considered an attractive target for Tp53 wild‐type acute myeloid leukaemia (AML) treatment. In this study, we evaluated the anti‐tumour effect of Csnk1a1 suppression in GBM cells in vitro and in vivo. We found that down‐regulation of Csnk1a1 or inhibition by D4476, a Csnk1a1 inhibitor, reduced GBM cell proliferation efficiently in both Tp53 wild‐type and Tp53‐mutant GBM cells. On the contrary, overexpression of Csnk1a1 promoted cell proliferation and colony formation. Csnk1a1 inhibition improved the sensitivity to radiotherapy. Furthermore, down‐regulation of Csnk1a1 reduced the production and secretion of pro‐inflammatory factors. In the preclinical GBM model, treatment with D4476 significantly inhibited the increase in pro‐inflammatory factors caused by radiotherapy and improved radiotherapy sensitivity, thus inhibiting tumour growth and prolonging animal survival time. These results suggest targeting Csnk1a1 exert an anti‐tumour role as an inhibitor of inflammatory factors, providing a new strategy for the treatment of glioma.