14-3-3σ regulation of and interaction with YAP1 in acquired gemcitabine resistance via promoting ribonucleotide reductase expression
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Li Qin1, Zizheng Dong1, Jian-Ting Zhang1
1Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA
Jian-Ting Zhang, e-mail: email@example.com
Keywords: 14-3-3σ, gemcitabine resistance, ribonucleotide reductase, YAP1, gene expression
Received: September 05, 2015 Accepted: January 23, 2016 Published: February 15, 2016
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.
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