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Excess growth hormone suppresses DNA damage repair in epithelial cells
Vera Chesnokova, … , Vera Gorbunova, Shlomo Melmed
Vera Chesnokova, … , Vera Gorbunova, Shlomo Melmed
Published February 7, 2019
Citation Information: JCI Insight. 2019;4(3):e125762. https://doi.org/10.1172/jci.insight.125762.
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Research Article Endocrinology

Excess growth hormone suppresses DNA damage repair in epithelial cells

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Abstract

Growth hormone (GH) decreases with age, and GH therapy has been advocated by some to sustain lean muscle mass and vigor in aging patients and advocated by athletes to enhance performance. Environmental insults and aging lead to DNA damage, which — if unrepaired — results in chromosomal instability and tumorigenesis. We show that GH suppresses epithelial DNA damage repair and blocks ataxia telangiectasia mutated (ATM) kinase autophosphorylation with decreased activity. Decreased phosphorylation of ATM target proteins p53, checkpoint kinase 2 (Chk2), and histone 2A variant led to decreased DNA repair by nonhomologous end-joining. In vivo, prolonged high GH levels resulted in a 60% increase in unrepaired colon epithelial DNA damage. GH suppression of ATM was mediated by induced tripartite motif containing protein 29 (TRIM29) and attenuated tat interacting protein 60 kDa (Tip60). By contrast, DNA repair was increased in human nontumorous colon cells (hNCC) where GH receptor (GHR) was stably suppressed and in colon tissue derived from GHR–/– mice. hNCC treated with etoposide and GH showed enhanced transformation, as evidenced by increased growth in soft agar. In mice bearing human colon GH-secreting xenografts, metastatic lesions were increased. The results elucidate a mechanism underlying GH-activated epithelial cell transformation and highlight an adverse risk for inappropriate adult GH treatment.

Authors

Vera Chesnokova, Svetlana Zonis, Robert Barrett, Hiraku Kameda, Kolja Wawrowsky, Anat Ben-Shlomo, Masaaki Yamamoto, John Gleeson, Catherine Bresee, Vera Gorbunova, Shlomo Melmed

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Figure 1

GH suppresses etoposide-induced DNA damage response (DDR) and increases unrepaired DNA damage.

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GH suppresses etoposide-induced DNA damage response (DDR) and increases ...
In all experiments, hNCC were pretreated with 500 ng/ml GH for 6 h and then treated with 5 μM etoposide (Etop). (A) Western blot of hNCC harvested 24 hours after etoposide treatment. (B) Western blot of hNCC harvested 1 and 3 hours after etoposide treatment. Shown are representative results from 3–5 independent experiments. For A and B, quantification of protein expression is depicted in Supplemental Figure 1, A and B. (C) Aggregate measurements of γH2AX foci in hNCC harvested 24 hours after etoposide treatment. One dot represents measurements in a single nucleus; 20–30 nuclei per image and 5 images per group were analyzed. Differences were assessed by nonparametric Wilcoxon rank sum test.

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