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.

Endocrinology
|April 20, 2019
PubMed

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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