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.

• Authors: Guanzheng Liu, Huan Li, Wanhong Zhang, Jiefeng Yu, Xu Zhang, Runqiu Wu, Mingshan Niu, Xuejiao Liu, Rutong Yu
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 25 Issue 15 Pg. 7395-7406 (08 2021) ISSN: 1582-4934 [Electronic] England
• PMID: 34216174 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Interleukin-6
• Tumor Suppressor Protein p53
• Casein Kinase Ialpha

Topics

• Animals
• Brain Neoplasms (metabolism, pathology, radiotherapy)
• Casein Kinase Ialpha (antagonists & inhibitors, genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Down-Regulation
• Glioma (metabolism, pathology, radiotherapy)
• Humans
• Interleukin-6 (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Radiation Tolerance
• Tumor Suppressor Protein p53 (genetics)