Casein kinase 1α 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 1α (CK1α), encoded by CSNK1A1, regulates Wnt/β-catenin, p53 and other key signaling pathways, and is critically involved in tumor progression. However, the relationship and mechanism of CK1α 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 CK1α was a negative regulator of autophagy and apoptosis. Pharmacologic inhibition of CK1α using D4476 or CK1α 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. CK1α interacted with murine double minute 2 (MDM2) and p53, and CK1α 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 CK1α promotes AML by suppressing p53 downstream of MDM2-mediated autophagy and apoptosis, suggesting that targeting CK1α provides a therapeutic opportunity to treat AML.

Casein Kinase-1-Alpha Inhibitor (D4476) Sensitizes Microsatellite Instable Colorectal Cancer Cells to 5-Fluorouracil via Authophagy Flux Inhibition

“…In this regard, it was found that CK1α inhibition led to the overexpression of autophagy genes in RAS-mutated colon cancer cell lines (Cheong et al 2015) through stabilization of transcription factor FOXO3a (regulator of autophagic flux). Recently, CK1α has been recognized as a negative regulator of oncogenic RAS-induced autophagy, further strengthening our argument that CK1αregulated autophagy can be a promising therapeutic target (Xu et al 2020). Carrino et al (2019), suggested that CK1α inhibition with the CK1α inhibitor D4476 resulted in impaired degradation of autophagosomes in multiple myeloma, which was likely related to its effect on the acidification of the lysosomes.…”

Targeting Protein Kinases in Blood Cancer: Focusing on CK1α and CK2

“…In MM, CK1α inhibits p53 and prevents the caspase-mediated degradation of AKT and β-catenin, promoting a cell-survival advantage [ 24 ]. In AML, knockdown or downregulation of CK1α correlates with increased expression of a p53 signature [ 21 ], and a more recent study reports that the blockage of p53 by CK1α prevents autophagy activation [ 101 ].…”

“…Recently, it has been reported that, in AML, CK1α exerts an opposite role in autophagy regulation, via the inhibition of p53/MDM2-mediated autophagy. Both pharmacological and genetic inhibition of CK1α induced autophagy and apoptosis in AML cell lines and patient blast cells [ 101 ]. Thus, the influence of CK1α on autophagy may be cell type and/or disease context dependent.…”

TP53 signal pathway confers potential therapy target in acute myeloid leukemia

“…21 In addition, several other regulators mediate MDM2, such as CK1α, and were also observed to affect the p53 signal pathway by inhibiting MDM2-mediated autophagy and apoptosis. 23 (Figure 2).…”