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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Categories: Research Article Endocrinology

Excess growth hormone suppresses DNA damage repair in epithelial cells

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 8

GH decreases survival but increases anchorage-independent growth and metastasis.

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GH decreases survival but increases anchorage-independent growth and met...
(A) Number of colonies per well in hNCC pretreated with 500 ng/ml for 6 hours and treated with etoposide for 1, 3, and 24 hours and normalized to number of colonies in etoposide-only treated cells (control). The number of colonies was assessed 8 days later, and assays were performed in triplicate. Results shown are mean ± SEM of 3 independent experiments. Controls represent untreated cells. (B) Number of colonies formed by hNCC in soft agar treated as in A with 100 and 500 ng/ml GH. Results shown are mean ± SEM of duplicates in 4 independent experiments. In A and B, differences were assessed with Tukey-adjusted mixed model regression. Controls represent cells treated with etoposide only. (C–D) Athymic nude mice were injected with HCT116 lenti mGH (GH) or HCT116 lenti vector (vector) cells. Four weeks later, when mice develop ~0.53 cm xenograft tumors, they received intrasplenic injections of 500,000 HCT116 cells and were sacrificed 4 weeks later. (C) Percent of mice that developed distant metastasis. (D) Number of metastases per mouse adjusted to the circulating GH levels. One-way ANCOVA, F = 4.66, degrees of freedom = 1.16, P = 0.045.