Csnk1a1 inhibition modulates the inflammatory secretome and enhances response to radiotherapy in glioma.
Guanzheng LiuHuan LiWanhong ZhangJiefeng YuXu ZhangRunqiu WuMingshan NiuXuejiao LiuRutong YuPublished in: Journal of cellular and molecular medicine (2021)
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.
Keyphrases
- early stage
- wild type
- cell proliferation
- poor prognosis
- locally advanced
- radiation therapy
- radiation induced
- induced apoptosis
- oxidative stress
- stem cells
- long non coding rna
- acute myeloid leukemia
- combination therapy
- bone marrow
- dendritic cells
- gene expression
- rectal cancer
- liver failure
- copy number
- replacement therapy
- white matter
- free survival