Excess growth hormone suppresses DNA damage repair in epithelial cells
Excess growth hormone suppresses DNA damage repair in epithelial cells
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DOI：
10.1172/jci.insight.125762
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发表时间：
2019-02-07
期刊：
影响因子：
8
通讯作者：
Melmed, Shlomo
中科院分区：
文献类型：
--
作者：
Chesnokova, Vera;Zonis, Svetlana;Melmed, Shlomo
生长激素（GH）随着年龄的增长而减少，一些人主张GH治疗可以维持老年患者的瘦肌肉质量和活力，运动员也主张GH治疗可以提高表现。环境损伤和老化导致DNA损伤，如果不修复，会导致染色体不稳定和肿瘤发生。我们发现，生长激素抑制上皮细胞DNA损伤修复和阻断共济失调毛细血管扩张症突变（ATM）激酶自磷酸化活性降低。ATM靶蛋白p53、检查点激酶2（Chk 2）和组蛋白2A变体的磷酸化减少导致非同源末端连接的DNA修复减少。在体内，长期高GH水平导致未修复的结肠上皮DNA损伤增加60%。GH对ATM的抑制作用是由诱导的三重基序蛋白29（TRIM 29）和减弱的达特相互作用蛋白60 kDa（Tip 60）介导的。相比之下，在GH受体（GHR）被稳定抑制的人非肿瘤结肠细胞（hNCC）和GHR（-/-）小鼠的结肠组织中，DNA修复增加。用依托泊苷和GH处理的hNCC显示增强的转化，如在软琼脂中增加的生长所证明的。在携带人结肠GH分泌异种移植物的小鼠中，转移性病变增加。结果阐明了GH激活上皮细胞转化的机制，并强调了不适当的成人GH治疗的不良风险。
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.