title: PDGF-BB and bFGF ameliorate radiation-induced intestinal progenitor/stem cell apoptosis via Akt/p53 signaling in mice.
abstract: Radiation-induced gastrointestinal (GI) syndrome currently has no effective prophylactic or therapeutic treatment. Previous studies and our data have demonstrated the important role of p53 in acute radiation-induced GI syndrome in mice. Many cytokines, such as tumor necrosis factor-α and fibroblast growth factor (bFGF), have been found to protect against radiation-induced intestinal injury, although the underlying mechanisms remain to be identified. Here, we report blockage of p53 through a protein kinase B (Akt) pathway in intestinal progenitor/stem cells or crypt cells as a novel molecular mechanism of growth factor-mediated intestinal radioprotection. Treatment with platelet-derived growth factor (PDGF-BB) or bFGF activated Akt phosphorylation in the intestinal crypt, lessened intestinal crypt p53 expression, decreased radiation-induced apoptosis in mouse intestinal progenitor/stem cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)-positive cells by an average of 50%, and increased the survival rate of mice with abdominal radiation by 3 days in average. Conversely, the Akt inhibitor perifosine obstructed growth factor-simulated Akt phosphorylation while promoting radiation-induced p53 expression in intestinal crypts. Importantly, reduced Akt phosphorylation and elevated p53 expression due to the Akt inhibitor perifosine impaired intestinal progenitor/stem cells radioprotection provided by PDGF-BB and bFGF. Consistently, PDGF-BB and bFGF both upregulated Akt activation, suppressed radiation-induced p53 expression, and abrogated radiation-induced apoptosis in IEC-6 cells, although p53 overexpression in IEC-6 cells partially counteracted the radioprotection of PDGF-BB and bFGF. Our data suggest that intestinal crypt radioprotection by PDGF-BB and bFGF is dependent on regulation of Akt/p53 signaling.
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Siwei
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Yashi
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China binwu001@hotmail.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D000077214:Becaplermin; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D007422:Intestines / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects*; D051379:Mice; D051058:Oncogene Protein v-akt / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D011837:Radiation-Protective Agents; D016159:Tumor Suppressor Protein p53; D016222:Fibroblast Growth Factor 2; D000077214:Becaplermin; D051058:Oncogene Protein v-akt
keywords: Akt; PDGF-BB; bFGF; intestinal apoptosis; p53