title: Amifostine alleviates radiation-induced lethal small bowel damage via promotion of 14-3-3σ-mediated nuclear p53 accumulation.
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.
authors.affiliation: Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Niao-Sung District, Kaohsiung 833, Taiwan. Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taiwan. School of Traditional Chinese Medicine, Chang Gung University College of Medicine, Taiwan.
authors.forename: Eng-Yen
authors.initials: EY
authors.lastname: Huang
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taiwan. Department of Medical Research, Niao-Sung District, Kaohsiung 833, Taiwan. Center for Laboratory Animals, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niao-Sung District, Kaohsiung 833, Taiwan.
authors.forename: Feng-Sheng
authors.initials: FS
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Niao-Sung District, Kaohsiung 833, Taiwan.
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Niao-Sung District, Kaohsiung 833, Taiwan.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Niao-Sung District, Kaohsiung 833, Taiwan.
authors.forename: Chung-Chi
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Niao-Sung District, Kaohsiung 833, Taiwan.
authors.forename: I-Hui
authors.initials: IH
authors.lastname: Lin
authors.affiliation: Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Niao-Sung District, Kaohsiung 833, Taiwan.
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Huang
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taiwan. Department of Medical Research, Show Chwan Memorial Hospital in Chang Bing, Chang Bing Industrial Center, Lu-Kang, Changhua 505, Taiwan. Institute of Clinical Medicine, National Yang Ming University, Taiwan.
authors.forename: Kuender D
authors.initials: KD
authors.lastname: Yang
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D011837:Radiation-Protective Agents; D016159:Tumor Suppressor Protein p53; D004999:Amifostine