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01-07-2019 | Breast Cancer | Preclinical study

Regulation of AKT phosphorylation by GSK3β and PTEN to control chemoresistance in breast cancer

Authors: Chunyi Gao, Xiaoyu Yuan, Zhenglin Jiang, Deqiang Gan, Lingzhi Ding, Yechao Sun, Jiamin Zhou, Lihua Xu, Yifei Liu, Guohua Wang

Published in: Breast Cancer Research and Treatment | Issue 2/2019

Abstract

Background

Phosphorylated AKT is highly expressed or overexpressed in chemoresistant tumor samples. However, the precise molecular mechanism involved in AKT phosphorylation-related chemoresistance in breast cancer is still elusive. The present research was designed to estimate the effect of AKT phosphorylation on cell viability and chemoresistance in breast cancer.

Methods

We utilized MCF-7 and MDA-MB468 human breast cancer cell lines and developed multidrug-resistant MCF-7/MDR and cisplatin-resistant MDA-MB-468 cells. Immunofluorescence analysis and Western blotting were employed to test the level of glycogen synthase kinase 3 beta (GSK3β), phosphorylated phosphatase and tension homologue (p-PTEN) and phosphorylated AKT (p-AKT) in MCF-7/MDR and MDA-MB468 cells. Xenograft assays in nude mice were performed with MCF-7/MDR cells to verify chemoresistance and the signaling pathway upstream of phosphatidylinositide 3-kinase (PI3K)/AKT.

Results

An increase in GSK3β, p-PTEN and p-AKT expression was strongly induced in MCF-7/MDR and cisplatin-resistant MDA-MB-468 cells, and augmented GSK3β phosphorylation and PTEN inactivation enhanced AKT signaling. The elevation in GSK3β, p-PTEN and p-AKT was associated with cell viability based on a CCK-8 assay. The results of in vivo and in vitro assays indicated that GSK3β knockdown with lentiviral shRNA (shRNA-GSK3β) promoted apoptosis and suppressed the migration of cisplatin-resistant MCF-7/MDR cells, while these effects were reversed by activating p-AKT with the PTEN inhibitor bpV(pic).

Conclusions

AKT phosphorylation mediated by GSK3β and PTEN were correlated with cell viability, migration and apoptosis, which may promote chemoresistance in breast cancer. Furthermore, GSK3β can regulate cell viability through the PTEN/PI3K/AKT signaling pathway and induce chemoresistance, serving as a valuable molecular strategy for breast cancer therapy.

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Title: Regulation of AKT phosphorylation by GSK3β and PTEN to control chemoresistance in breast cancer
Authors: Chunyi Gao
Xiaoyu Yuan
Zhenglin Jiang
Deqiang Gan
Lingzhi Ding
Yechao Sun
Jiamin Zhou
Lihua Xu
Yifei Liu
Guohua Wang
Publication date: 01-07-2019
Publisher: Springer US
Keywords: Breast Cancer
Breast Cancer
Published in: Breast Cancer Research and Treatment / Issue 2/2019
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-019-05239-3

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