Abstract
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 PUMA in acute radiation-induced GI damage and GI syndrome in mice. Growth factors such as IGF-1 and 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 PI3K/AKT/p53 axis in the intestinal stem cells (ISCs) as a novel molecular mechanism of growth factor-mediated intestinal radioprotection. IGF-I 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 following radiation.
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