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

Oncogene volume 29, pages 1622–1632 (2010)Cite this article

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 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.

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Abbreviations

AKT:

protein kinase B

bFGF:

basic fibroblast growth factor

IGF-1:

insulin-like growth factor 1

ISCs:

intestinal stem cells

JNK:

c-Jun N-terminal kinase

KO:

knockout

MAPK:

mitogen-activated protein kinase

PBS:

phosphate-buffered saline

PI3K:

phosphoinositide 3-kinase

PUMA:

p53 upregulated modulator of apoptosis

TUNEL:

terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick end labeling

WT:

wildtype

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Acknowledgements

We thank other members of our labs for helpful discussion and advice and Ms Hong Tao Liu for breeding mice. This work is supported in part by NIH grants CA106348, CA121105, and American Cancer Society grant RSG-07-156-01-CNE (L Zhang), and NIH grants CA129829, UO1-DK085570, U19-A1068021 (pilot project), and those from ACGT and FAMRI (J Yu).

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Authors and Affiliations

  1. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    W Qiu, B Leibowitz, L Zhang & J Yu

  2. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    W Qiu, B Leibowitz & J Yu

  3. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    L Zhang

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  1. W Qiu
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  2. B Leibowitz
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Correspondence to J Yu.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Qiu, W., Leibowitz, B., Zhang, L. et al. Growth factors protect intestinal stem cells from radiation-induced apoptosis by suppressing PUMA through the PI3K/AKT/p53 axis. Oncogene 29, 1622–1632 (2010). https://doi.org/10.1038/onc.2009.451

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