Open Access

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

  • Authors:
    • Wanling Xu
    • Ziyang Huang
    • Yifeng Gan
    • Rongrong Chen
    • Yisha Huang
    • Bin Xue
    • Songfu Jiang
    • Zhijie Yu
    • Kang Yu
    • Shenghui Zhang
  • View Affiliations

  • Published online on: September 9, 2020     https://doi.org/10.3892/or.2020.7760
  • Pages: 1895-1904
  • Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.
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November-2020
Volume 44 Issue 5

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Xu W, Huang Z, Gan Y, Chen R, Huang Y, Xue B, Jiang S, Yu Z, Yu K, Zhang S, Zhang S, et al: Casein kinase 1α inhibits p53 downstream of MDM2‑mediated autophagy and apoptosis in acute myeloid leukemia. Oncol Rep 44: 1895-1904, 2020
APA
Xu, W., Huang, Z., Gan, Y., Chen, R., Huang, Y., Xue, B. ... Zhang, S. (2020). Casein kinase 1α inhibits p53 downstream of MDM2‑mediated autophagy and apoptosis in acute myeloid leukemia. Oncology Reports, 44, 1895-1904. https://doi.org/10.3892/or.2020.7760
MLA
Xu, W., Huang, Z., Gan, Y., Chen, R., Huang, Y., Xue, B., Jiang, S., Yu, Z., Yu, K., Zhang, S."Casein kinase 1α inhibits p53 downstream of MDM2‑mediated autophagy and apoptosis in acute myeloid leukemia". Oncology Reports 44.5 (2020): 1895-1904.
Chicago
Xu, W., Huang, Z., Gan, Y., Chen, R., Huang, Y., Xue, B., Jiang, S., Yu, Z., Yu, K., Zhang, S."Casein kinase 1α inhibits p53 downstream of MDM2‑mediated autophagy and apoptosis in acute myeloid leukemia". Oncology Reports 44, no. 5 (2020): 1895-1904. https://doi.org/10.3892/or.2020.7760