Akt1 inhibition promotes breast cancer metastasis through EGFR-mediated β-catenin nuclear accumulation

Cell Communication and Signaling

Hua Sun¹  Jiu-Zhou Hou¹  Wei Li¹  Chang Ma¹  Qin Li¹  Jie Niu¹  Zhuo-Qing Xi¹  Dong Fang¹  Song-Qiang Xie²  Chao-Jie Wang³ 

[1] Institute for innovative drug design and evaluation, School of Pharmacy, Henan University;Institute of Chemical Biology, School of Pharmacy, Henan University;The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University;

关键词: Akt1;    EGFR;    β-Catenin;    PIKfyve;    Metastasis;   

DOI  :  10.1186/s12964-018-0295-1

来源: DOAJ

【 摘 要 】

Abstract Background Knockdown of Akt1 promotes Epithelial-to-Mesenchymal Transition in breast cancer cells. However, the mechanisms are not completely understood. Methods Western blotting, immunofluorescence, luciferase assay, real time PCR, ELISA and Matrigel invasion assay were used to investigate how Akt1 inhibition promotes breast cancer cell invasion in vitro. Mouse model of lung metastasis was used to measure in vivo efficacy of Akt inhibitor MK2206 and its combination with Gefitinib. Results Knockdown of Akt1 stimulated β-catenin nuclear accumulation, resulting in breast cancer cell invasion. β-catenin nuclear accumulation induced by Akt1 inhibition depended on the prolonged activation of EGFR signaling pathway in breast cancer cells. Mechanistic experiments documented that knockdown of Akt1 inactivates PIKfyve via dephosphorylating of PIKfyve at Ser318 site, resulting in a decreased degradation of EGFR signaling pathway. Inhibition of Akt1 using MK2206 could induce an increase in the expression of EGFR and β-catenin in breast cancer cells. In addition, MK2206 at a low dosage enhance breast cancer metastasis in a mouse model of lung metastasis, while an inhibitor of EGFR tyrosine kinase Gefitinib could potentially suppress breast cancer metastasis induced by Akt1 inhibition. Conclusion EGFR-mediated β-catenin nuclear accumulation is critical for Akt1 inhibition-induced breast cancer metastasis.

【 授权许可】

Unknown