title: Chemotherapy mediates intestinal injury via p53/p53 upregulated modulator of apoptosis (PUMA) signaling pathway.
abstract: OBJECTIVE
  The aim of this study was to investigate the potential mechanism and signaling pathway involved in chemotherapy-induced intestinal mucosal injury (CIMI), which is a common physiopathological problem in patients with cancer.
  
  
  METHODS
  For the in vivo experiment, mice received intraperitoneal injection of 5-fluorouracil (5-FU) at a dose of 75 mg/kg/day for 1, 3 or 5 days. Villus height and crypt depth of the small intestine, cell apoptosis and proliferation were then examined to determine the extent of CIMI. The expressions of Akt, p53, PUMA and p21 were evaluated both in vivo in mice models and in vitro in the IEC-6 and HCT116 cell lines.
  
  
  RESULTS
  After 5-FU therapy both the intestinal villus height (275.93 μm vs 164.52 μm, P < 0.001) and crypt depth (64.13 μm vs 42.48 μm, P < 0.001) were decreased. The apoptotic index was greatly increased from 0.32% to 15.84% (P < 0.001) and proliferation was suppressed (63.58% vs 39.15%, P < 0.001). Additionally, p53 expression was significantly increased in the intestinal crypt along with the expressions of PUMA and p21. Western blot showed that the administration of 5-FU induced p53/PUMA-mediated apoptosis and upregulated p21 expression to suppress cell proliferation.
  
  
  CONCLUSIONS
  Chemotherapy might mediate intestinal injury via p53/PUMA-mediated apoptotic signaling and the suppression of proliferation in response to p21.
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China.
authors.forename: Ya Shi
authors.initials: YS
authors.lastname: Zhan
authors.forename: Si Wei
authors.initials: SW
authors.lastname: Tan
authors.forename: Wei
authors.initials: W
authors.lastname: Mao
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.forename: Hui Ling
authors.initials: HL
authors.lastname: Liu
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000633:toxicity*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052016:Mucositis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*
chemical_list: D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D005472:Fluorouracil
keywords: chemotherapy; fluorouracil; neoplasm; p53-upregulated modulator of apoptosis; small intestine; tumor suppressor protein p53