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

Abstract

BackgroundKnockdown of Akt1 promotes Epithelial-to-Mesenchymal Transition in breast cancer cells. However, the mechanisms are not completely understood.MethodsWestern 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.ResultsKnockdown 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.ConclusionEGFR-mediated β-catenin nuclear accumulation is critical for Akt1 inhibition-induced breast cancer metastasis.

Suppression of epidermal growth factor receptor‐mediated β‐catenin nuclear accumulation enhances the anti‐tumor activity of phosphoinositide 3‐kinase inhibitor in breast cancer

“…EGFR activation usually initiates β‐catenin nuclear accumulation in tumor development (Yang et al, ; Ji et al, ). AKT inhibition increases EGFR activation through a negative feedback loop in breast cancer cells (Er et al, ; Li et al, ). Since PI3K is one of the dominant upstream molecules of Akt signaling (Lee et al, ), therefore, we speculated that PI3K inhibitor LY294002‐induced β‐catenin nuclear accumulation is dependent upon the activation of EGFR in breast cancer cells.…”

“…Epidermal growth factor receptor (EGFR) overexpression in breast cancer is known to be associated with proliferation, survival, and migration of cancer cells (Wee and Wang, 2017;Li et al, 2018;Sigismund et al, 2018). Several studies suggested that breast cancer cells confer resistance to PI3K Cell Biol Int 43 (2019) 931-939 © 2019 International Federation for Cell Biology inhibitors by reactivating EGFR signaling pathways through a negative feedback loop (Stratikopoulos et al, 2015;Timmermans-Sprang et al, 2015).…”

LncRNA EIF3J-AS1 enhanced esophageal cancer invasion via regulating AKT1 expression through sponging miR-373-3p

“…We could prove the suppression of AKT1 by miR-373-3p in ECa cell lines. AKT1 was an oncogene in several cancer diseases including osteosarcoma, pancreatic ductal adenocarcinoma, colorectal cancer, and breast cancer [32][33][34][35] .Recently, lncRNAs have been implicated in the miRNA/AKT1 axis modulation in www.nature.com/scientificreports/ human cancers. For instance, the LINC00324 counteract miR-615-5p and enhance the expression of AKT1 in lung adenocarcinoma 36 .…”

Antihypertensive Activity of Eucommia Ulmoides Oliv: Male Flower Extract in Spontaneously Hypertensive Rats

“…Western blot analysis was conducted as previously described [16]. Briefly, the total proteins were extracted from left ventricles using ice-chilled RIPA lysis buffer containing 50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 0.5% sodium deoxycholate, 0.1% SDS, 1% NP-40, 5 mM EDTA, 0.25 mM PMSF, and protease inhibitor cocktail.…”