Casein kinase 1? inhibits p53 downstream of MDM2?mediated autophagy and apoptosis in acute myeloid leukemia.

ABSTRACT: Enhancement of autophagy serves as a promising therapeutic strategy for cancer, including acute myeloid leukemia (AML). Casein kinase 1? (CK1?), encoded by CSNK1A1, regulates Wnt/??catenin, p53 and other key signaling pathways, and is critically involved in tumor progression. However, the relationship and mechanism of CK1? with autophagy in AML still remain unclear. In the present study, it was found that AML patients had higher expression of CSNK1A1 mRNA than healthy donors. Furthermore, we analyzed 163 cases of AML patients in the LAML database of TCGA and found that AML patients with high CSNK1A1 had shorter overall survival than those with low or medium CSNK1A1 expression. Furthermore, we demonstrated that CK1? was a negative regulator of autophagy and apoptosis. Pharmacologic inhibition of CK1? using D4476 or CK1? knockdown via lentivirus?mediated shRNA suppressed proliferation and the clone formation by enhancing autophagic flux and apoptosis in AML cell lines as well as in patient blast cells. Intriguingly, D4476?induced cell death was aggravated in combination with an autophagy inhibitor, Spautin?1, suggesting that autophagy may be a pro?survival signaling. CK1? interacted with murine double minute 2 (MDM2) and p53, and CK1? inhibitor D4476 significantly upregulated p53 and phosphorylated 5' AMP?activated protein kinase (AMPK), and substantially inhibited the phosphorylation of mammalian target of rapamycin (mTOR). Our findings indicate that CK1? promotes AML by suppressing p53 downstream of MDM2?mediated autophagy and apoptosis, suggesting that targeting CK1? provides a therapeutic opportunity to treat AML.

SUBMITTER: Xu W 

PROVIDER: S-EPMC7550986 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature