Growth factors protect intestinal stem cells from radiation-induced apoptosis by suppressing PUMA through the PI3K AKT p53 axis

• Published in: Oncogene Vol. 29; no. 11; pp. 1622 - 1632
• Main Authors: Qiu, W, Leibowitz, B, Zhang, L, Yu, J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-03-2010; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; Ageing, cell death; AKT protein; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - radiation effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biological and medical sciences; Blotting, Western; Cell Biology; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Epithelial cells; Female; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - pharmacology; Fundamental and applied biological sciences. Psychology; Gastroenterology; Gastrointestinal diseases; Genetics; Growth factors; HCT116 Cells; Health aspects; Human Genetics; Humans; In Situ Nick-End Labeling; Insulin; Insulin-like growth factor I; Insulin-Like Growth Factor I - pharmacology; Insulin-like growth factors; Intercellular Signaling Peptides and Proteins - pharmacology; Internal Medicine; Intestinal Mucosa - metabolism; Intestine; Intestines - cytology; Kinases; Male; MDM2 protein; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular and cellular biology; Oncology; original-article; p53 Protein; Phosphatidylinositol 3-Kinases - metabolism; Physiological aspects; Protein kinases; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Radiation; Radiation protection; Radiation therapy; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; Signal Transduction - drug effects; Signal Transduction - radiation effects; Stem cell transplantation; Stem cells; Stem Cells - drug effects; Stem Cells - metabolism; Stem Cells - radiation effects; Toxicity; Tumor Suppressor Protein p53 - metabolism; United States; apoptosis; growth factors; PI3K; PUMA; intestinal stem cells; p53; Digestive system; Stem cell; Gut; Akt protein kinase; Carcinogenesis; TP53 Gene; Irradiation; Apoptosis; Growth factor; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.451

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.