14-3-3σ regulation of and interaction with YAP1 in acquired gemcitabine resistance via promoting ribonucleotide reductase expression.

Li Qin,Jian-Ting Zhang,Zizheng Dong

doi:10.18632/oncotarget.7394

Abstract

Gemcitabine is an important anticancer therapeutics approved for treatment of several human cancers including locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Its clinical effectiveness, however, is hindered by existence of intrinsic and development of acquired resistances. Previously, it was found that 14-3-3σ expression associates with poor clinical outcome of PDAC patients. It was also found that 14-3-3σ expression is up-regulated in gemcitabine resistant PDAC cells and contributes to the acquired gemcitabine resistance. In this study, we investigated the molecular mechanism of 14-3-3σ function in gemcitabine resistance and found that 14-3-3σ up-regulates YAP1 expression and then binds to YAP1 to inhibit gemcitabine-induced caspase 8 activation and apoptosis. 14-3-3σ association with YAP1 up-regulates the expression of ribonucleotide reductase M1 and M2, which may mediate 14-3-3σ/YAP1 function in the acquired gemcitabine resistance. These findings suggest a possible role of YAP1 signaling in gemcitabine resistance.

Highlights

Gemcitabine is a deoxycytidine analogue approved as the first-line chemotherapeutic drug for patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) [1, 2], one of the cancers having poorest prognosis with 5-year survival rate hovering only around 7% [3]
Using a newly established gemcitabine resistant PDAC cell line, G3K derived from MiaPaCa-2 cells via stepwise gemcitabine selections, we showed that 14-3-3σ expression is upregulated via epigenetic regulation and contributes to the acquired gemcitabine resistance in the gemcitabine-selected PDAC G3K cells [8]
Because 14-3-3σ expression is up-regulated in G3K cells (Figure 1A), we investigated if 14-3-3σ and YAP1 expression is related by first knocking down 14-33σ in G3K cells and testing its effect on YAP1 expression

Summary

Introduction

Gemcitabine is a deoxycytidine analogue approved as the first-line chemotherapeutic drug for patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) [1, 2], one of the cancers having poorest prognosis with 5-year survival rate hovering only around 7% [3]. One of the major causes for the poor prognosis of PDAC is that it is intrinsically resistant or can acquire resistance to treatments including gemcitabine. Using a newly established gemcitabine resistant PDAC cell line, G3K derived from MiaPaCa-2 cells via stepwise gemcitabine selections, we showed that 14-3-3σ expression is upregulated via epigenetic regulation and contributes to the acquired gemcitabine resistance in the gemcitabine-selected PDAC G3K cells [8]. 14-3-3σ is known to belong to the highly conserved 143-3 protein family that binds to many phosphoserine/ phosphothreonine proteins important in multiple biological processes such as signal transduction, cell cycle control, and survival [11,12,13,14], how its increased expression contributes to acquired drug resistance in general and gemcitabine resistance is largely unknown

Methods

Results

Conclusion