Akt1 抑制通过 EGFR 介导的β-catenin 核积累促进乳腺癌转移。

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

机构信息

Institute for innovative drug design and evaluation, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China.

The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, N. Jinming Ave, Kaifeng, 475004, China.

出版信息

Cell Commun Signal. 2018 Nov 16;16(1):82. doi: 10.1186/s12964-018-0295-1.

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 Ser 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.

背景

Akt1 的敲低促进乳腺癌细胞发生上皮间质转化。然而，其机制尚不完全清楚。

方法

采用 Western blot、免疫荧光、荧光素酶报告基因检测、实时定量 PCR、ELISA 和基质胶侵袭实验，研究 Akt1 抑制如何促进乳腺癌细胞体外侵袭。利用小鼠肺转移模型，检测 Akt 抑制剂 MK2206 及其与吉非替尼联合应用的体内疗效。

结果

Akt1 的敲低刺激β-连环蛋白入核，导致乳腺癌细胞侵袭。Akt1 抑制诱导的β-连环蛋白入核依赖于乳腺癌细胞中 EGFR 信号通路的持续激活。机制研究表明，Akt1 的敲低通过磷酸酶 PIKfyve 的 Ser 位点去磷酸化使其失活，从而导致 EGFR 信号通路降解减少。MK2206 抑制 Akt1 可诱导乳腺癌细胞中 EGFR 和 β-连环蛋白表达增加。此外，MK2206 在低剂量时可增强小鼠肺转移模型中的乳腺癌转移，而 EGFR 酪氨酸激酶抑制剂吉非替尼可潜在抑制 Akt1 抑制诱导的乳腺癌转移。