Oncotarget

Research Papers:

Reduced RKIP enhances nasopharyngeal carcinoma radioresistance by increasing ERK and AKT activity

Li Yuan, Hong-Mei Yi, Hong Yi, Jia-Quan Qu, Jin-Feng Zhu, Li-Na Li, Ta Xiao, Zhen Zheng, Shan-Shan Lu and Zhi-Qiang Xiao _

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Oncotarget. 2016; 7:11463-11477. https://doi.org/10.18632/oncotarget.7201

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Abstract

Li Yuan1,2, Hong-Mei Yi1,2, Hong Yi1,2, Jia-Quan Qu1,2, Jin-Feng Zhu1,2, Li-Na Li1,2, Ta Xiao1,2, Zhen Zheng1,2, Shan-Shan Lu1,2, Zhi-Qiang Xiao1,2

1Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China

2The Higher Educational Key Laboratory for Cancer Proteomics and Translational Medicine of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China

Correspondence to:

Zhi-Qiang Xiao, e-mail: [email protected]

Keywords: nasopharyngeal carcinoma, radioresistance, RKIP, ERK−1/2, AKT

Received: October 06, 2015     Accepted: January 15, 2016     Published: February 05, 2016

ABSTRACT

Raf kinase inhibitory protein (RKIP) functions as a chemo-immunotherapeutic sensitizer of cancers, but regulation of RKIP on tumor radiosensitivity remains largely unexplored. In this study, we investigate the role and mechanism of RKIP in nasopharyngeal carcinoma (NPC) radioresistance. The results showed that RKIP was frequently downregulated in the radioresistant NPC tissues compared with radiosensitive NPC tissues, and its reduction correlated with NPC radioresistance and poor patient survival, and was an independent prognostic factor. In vitro radioresponse assay showed that RKIP overexpression decreased while RKIP knockdown increased NPC cell radioresistance. In the NPC xenografts, RKIP overexpression decreased while RKIP knockdown increased tumor radioresistance. Mechanistically, RKIP reduction promoted NPC cell radioresistance by increasing ERK and AKT activity, and AKT may be a downstream transducer of ERK signaling. Moreover, the levels of phospho-ERK−1/2 and phospho-AKT were increased in the radioresistant NPC tissues compared with radiosensitive ones, and negatively associated with RKIP expression, indicating that RKIP-regulated NPC radioresponse is mediated by ERK and AKT signaling in the clinical samples. Our data demonstrate that RKIP is a critical determinant of NPC radioresponse, and its reduction enhances NPC radioresistance through increasing ERK and AKT signaling activity, highlighting the therapeutic potential of RKIP-ERK-AKT signaling axis in NPC radiosensitization.


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