Growth factors protect intestinal stem cells from radiation-induced apoptosis by suppressing PUMA through the PI3K/AKT/p53 axis.
Gastrointestinal toxicity is the primary limiting factor in abdominal and pelvic radiotherapy, but has no effective treatment currently. We recently showed a critical role of the BH3-only protein p53 upregulated modulator of apoptosis (PUMA) in acute radiation-induced GI damage and GI syndrome in mice. Growth factors such as insulin-like growth factor 1 (IGF-1) and basic fibroblast growth factor (bFGF) have been shown to protect against radiation-induced intestinal injury, although the underlying mechanisms remain to be identified. We report here the suppression of PUMA through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/p53 axis in the intestinal stem cells as a novel molecular mechanism of growth factor-mediated intestinal radioprotection. IGF-1 or bFGF impaired radiation-induced apoptosis and the expression of PUMA and p53 in the crypt cells and intestinal stem cells. Using colonic epithelial cells that undergo PUMA-dependent and radiation-induced apoptosis, we found that a PI3K inhibitor, dominant-negative PI3K or Mdm2 antagonist restored the induction of PUMA, p53 and apoptosis in the presence of growth factors. In contrast, overexpression of AKT suppressed the induction of PUMA and p53 by radiation. Furthermore, inhibiting PI3K or activating p53 abrogated growth factor-mediated suppression of apoptosis and PUMA expression in the intestinal crypts and stem cells after radiation.
Qiu
W
W
University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Leibowitz
B
B
Zhang
L
L
Yu
J
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt