Issue 53, 2016

HDACI regulates the PI3K/Akt signaling pathway to reverse MCF-7/PTX resistance by inhibiting SET

Abstract

The occurrence of chemoresistance greatly restricts the efficacy of antitumor drugs, and so novel agents are urgently needed to abrogate resistant phenotypes. In this study we investigated the role of patient SE translation (SET) in the human breast cancer paclitaxel-resistant cell line (MCF-7/PTX) and the underlying reversal mechanism of FA18, a new synthetic histone deacetylase inhibitor. The expressions of SET, protein phosphatase 2A (PP2A), and factors related to the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and downstream mitochondrial apoptosis pathways were determined in MCF-7/PTX cells. In order to explore the role of SET in inducing drug resistance, a SET antagonist OP449 was used to down-regulate SET in MCF-7/PTX cells, and the cell viability, cell apoptosis, and pathway-related factors were assessed. Furthermore, the reversal effects of FA18 and its underlying mechanisms were investigated in vitro and in vivo. We found that SET and the PI3K/Akt signaling pathway were activated in MCF-7/PTX cells. The down-regulation of SET by OP449 significantly sensitized MCF-7/PTX cells to paclitaxel (PTX) and induced cell apoptosis. In addition, SET-induced PTX resistance was associated with activation of the PI3K/Akt signaling pathway and inhibition of mitochondrial apoptosis pathways. FA18 significantly reduced the mRNA and protein levels of SET in MCF-7/PTX cells. Furthermore, FA18 significantly inhibited SET-mediated resistance by attenuating the PI3K/Akt signaling pathway and activating mitochondrial apoptosis pathways. Additionally, FA18 significantly reduced the SET level via the PI3K/Akt signaling pathway both in vitro and in vivo. These results suggest that the overexpression of SET is associated with drug resistance in MCF-7/PTX cells. FA18 reversed this drug resistance, possibly via suppression of the SET/PI3K/Akt signaling pathway.

Graphical abstract: HDACI regulates the PI3K/Akt signaling pathway to reverse MCF-7/PTX resistance by inhibiting SET

Associated articles

Article information

Article type
Paper
Submitted
10 Mar 2016
Accepted
09 May 2016
First published
09 May 2016

RSC Adv., 2016,6, 48072-48082

HDACI regulates the PI3K/Akt signaling pathway to reverse MCF-7/PTX resistance by inhibiting SET

W. Zhang, X. Zheng, T. Meng, H. You, Y. Dong, J. Xing and S. Chen, RSC Adv., 2016, 6, 48072 DOI: 10.1039/C6RA06423J

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