Activation of AKT/AP1/FoxM1 signaling confers sorafenib resistance to liver cancer cells

  • Authors:
    • Dongjing Yan
    • Xiaojing Yan
    • Xufang Dai
    • Lingxi Chen
    • Liangbo Sun
    • Tao Li
    • Fengtian He
    • Jiqin Lian
    • Wangwei Cai
  • View Affiliations

  • Published online on: June 10, 2019     https://doi.org/10.3892/or.2019.7192
  • Pages: 785-796
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Abstract

Sorafenib is the first‑line drug used in the treatment of liver cancer; however, drug resistance seriously limits the clinical response to sorafenib. The present study investigated the molecular mechanisms of sorafenib resistance in liver cancer cells. The data indicated that forkhead box M1 (FoxM1) was significantly overexpressed in sorafenib‑resistant cells, at the mRNA and protein levels. Knockdown of FoxM1 rendered drug‑tolerant cells sensitive to sorafenib. Furthermore, FoxM1 was upregulated at the transcriptional level. Overexpression of c‑jun was associated with the upregulation of FoxM1. The results of a reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that there is an activator protein‑1 (AP1) binding site in the promoter of FoxM1, located at ‑608 to ‑618. Knockdown of c‑jun significantly decreased the levels of FoxM1, accompanied by enhanced cell sensitivity to sorafenib. Furthermore, the activation of AKT contributed to the upregulation of c‑jun and FoxM1. Inhibition of AKT using BEZ‑235 markedly suppressed the upregulation of c‑jun and FoxM1, and increased the sensitivity of drug‑resistant cells to sorafenib in vitro and in vivo. The data indicated that the activation of the AKT/AP1/FoxM1 signaling axis is an important determinant of sorafenib tolerance.

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August 2019
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Copy and paste a formatted citation
APA
Yan, D., Yan, X., Dai, X., Chen, L., Sun, L., Li, T. ... Cai, W. (2019). Activation of AKT/AP1/FoxM1 signaling confers sorafenib resistance to liver cancer cells. Oncology Reports, 42, 785-796. https://doi.org/10.3892/or.2019.7192
MLA
Yan, D., Yan, X., Dai, X., Chen, L., Sun, L., Li, T., He, F., Lian, J., Cai, W."Activation of AKT/AP1/FoxM1 signaling confers sorafenib resistance to liver cancer cells". Oncology Reports 42.2 (2019): 785-796.
Chicago
Yan, D., Yan, X., Dai, X., Chen, L., Sun, L., Li, T., He, F., Lian, J., Cai, W."Activation of AKT/AP1/FoxM1 signaling confers sorafenib resistance to liver cancer cells". Oncology Reports 42, no. 2 (2019): 785-796. https://doi.org/10.3892/or.2019.7192