Oncotarget

Research Papers:

Amifostine alleviates radiation-induced lethal small bowel damage via promotion of 14-3-3σ-mediated nuclear p53 accumulation

Eng-Yen Huang _, Feng-Sheng Wang, Yu-Min Chen, Yi-Fan Chen, Chung-Chi Wang, I-Hui Lin, Yu-Jie Huang and Kuender D. Yang

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Oncotarget. 2014; 5:9756-9769. https://doi.org/10.18632/oncotarget.2386

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Abstract

Eng-Yen Huang1,2,5,*, Feng-Sheng Wang2,3,4,*, Yu-Min Chen1, Yi-Fan Chen1, Chung-Chi Wang1, I-Hui Lin1, Yu-Jie Huang1, Kuender D. Yang2,6,7

1Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung District, Kaohsiung 833, Taiwan

2Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taiwan

3Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung District, Kaohsiung 833, Taiwan

4Center for Laboratory Animals, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung District, Kaohsiung 833, Taiwan

5School of Traditional Chinese Medicine, Chang Gung University College of Medicine, Taiwan

6Department of Medical Research, Show Chwan Memorial Hospital in Chang Bing, 6-1 Lu-Kung Road, Chang Bing Industrial Center, Lu-Kang, Changhua 505, Taiwan

7Institute of Clinical Medicine, National Yang Ming University, Taiwan

*These authors contributed equally to this work

Correspondence to:

Dr. Kuender D. Yang, e-mail: yangkd.yeh@hotmail.com

Keywords: amifostine, p53, small bowel, whole-abdominal irradiation, 14-3-3σ, MDM2

Received: June 29, 2014     Accepted: August 23, 2014     Published: September 23, 2014

ABSTRACT

Amifostine (AM) is a radioprotector that scavenges free radicals and is used in patients undergoing radiotherapy. p53 has long been implicated in cell cycle arrest for cellular repair after radiation exposure. We therefore investigated the protective p53-dependent mechanism of AM on small bowel damage after lethal whole-abdominal irradiation (WAI). AM increased both the survival rate of rats and crypt survival following lethal 18 Gy WAI. The p53 inhibitor PFT-α compromised AM-mediated effects when administered prior to AM administration. AM significantly increased clonogenic survival in IEC-6 cells expressing wild type p53 but not in p53 knockdown cells. AM significantly increased p53 nuclear accumulation and p53 tetramer expression before irradiation through the inhibition of p53 degradation. AM inhibited p53 interactions with MDM2 but enhanced p53 interactions with 14-3-3σ. Knockdown of 14-3-3σ also compromised the effect of AM on clonogenic survival and p53 nuclear accumulation in IEC-6 cells. For the first time, our data reveal that AM alleviates lethal small bowel damage through the induction of 14-3-3σ and subsequent accumulation of p53. Enhancement of the p53/14-3-3σ interaction results in p53 tetramerization in the nucleus that rescues lethal small bowel damage.


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