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Published on: June 9, 2020
Growth Hormone Induces Colon DNA Damage Independent of IGF-1
Vera Chesnokova1, Svetlana Zonis1, Robert J Barrett2
1Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
Abstract:
DNA damage occurs as a result of environmental insults and aging and, if unrepaired, may lead to chromosomal instability and tumorigenesis. Because GH suppresses ataxia-telangiectasia mutated kinase phosphorylation, decreases DNA repair, and increases DNA damage accumulation, we elucidated whether GH effects on DNA damage are mediated through induced IGF-1. In nontumorous human colon cells, GH, but not IGF-1, increased DNA damage. Stably disrupted IGF-1 receptor (IGF-1R) by lentivirus-expressing short hairpin RNA in vitro or treatment with the IGF-1R phosphorylation inhibitor picropodophyllotoxin (PPP) in vitro and in vivo led to markedly induced GH receptor (GHR) abundance, rendering cells more responsive to GH actions. Suppressing IGF-1R triggered DNA damage in both normal human colon cells and three-dimensional human intestinal organoids. DNA damage was further increased when cells with disrupted IGF-1R were treated with GH. Because GH induction of DNA damage accumulation appeared to be mediated not by IGF-1R but probably by more abundant GH receptor expression, we injected athymic mice with GH-secreting xenografts and then treated them with PPP. In these mice, high circulating GH levels were associated with increased colon DNA damage despite disrupted IGF-1R activity (P < 0.01), whereas GHR levels were also induced. Further confirming that GH effects on DNA damage are directly mediated by GHR signaling, GHR-/- mice injected with PPP did not show increased DNA damage, whereas wild-type mice with intact GHR exhibited increased colon DNA damage in the face of IGF-1 signaling suppression. The results indicate that GH directly induces DNA damage independent of IGF-1.
Insights
Growth hormone (GH) directly increases DNA damage in colon cells, independent of IGF-1 signaling. Suppressing the IGF-1 receptor enhances GH
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- DNA damage from environmental factors and aging can cause genomic instability and cancer.
- Growth hormone (GH) is known to suppress DNA repair mechanisms, potentially increasing DNA damage.
- The role of Insulin-like Growth Factor 1 (IGF-1) in mediating GH's effect on DNA damage requires clarification.
Purpose of the Study:
- To investigate whether GH-induced DNA damage is mediated by IGF-1.
- To explore the direct effects of GH on DNA damage in human colon cells.
- To elucidate the role of the GH receptor (GHR) and IGF-1 receptor (IGF-1R) in GH's impact on DNA damage.
Main Methods:
- In vitro studies using human colon cells with disrupted IGF-1R via short hairpin RNA.
- In vitro and in vivo experiments using the IGF-1R inhibitor picropodophyllotoxin (PPP).
- Xenograft mouse models with GH-secreting tumors and PPP treatment; analysis of GHR and IGF-1R activity.
- Comparison of DNA damage in GHR knockout (GHR-/-) and wild-type mice.
Main Results:
- GH, but not IGF-1 alone, increased DNA damage in normal human colon cells.
- Disrupting IGF-1R signaling led to increased GHR abundance and heightened cellular responsiveness to GH.
- GH treatment further exacerbated DNA damage in cells with suppressed IGF-1R.
- In vivo studies confirmed that GH increases colon DNA damage independently of IGF-1R activity, correlating with induced GHR levels.
- GHR knockout mice showed no increased DNA damage when IGF-1 signaling was suppressed, unlike wild-type mice.
Conclusions:
- GH directly induces DNA damage in colon cells, a process independent of IGF-1 signaling.
- The effects of GH on DNA damage are primarily mediated through the GH receptor (GHR), not the IGF-1 receptor (IGF-1R).
- Suppression of IGF-1R signaling can potentiate GH-induced DNA damage by upregulating GHR expression.
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