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Somatotropinomas, but not nonfunctioning pituitary adenomas, maintain a functional apoptotic RET/Pit1/ARF/p53 pathway

Esther Diaz-Rodriguez1, Angela R Garcia-Rendueles, Alejandro Ibáñez-Costa

  • 1Centre for Investigations in Medicine of the USC (E.D.-R., A.R.G.-G., M.G.-L., C.D., C.V.A.), University of Santiago de Compostela, Santiago de Compostela, Spain 15782; Department of Endocrinology (I.B.), University Hospital (University Hospital of Santiago de Compostela), Instituto de Investigación Sanitaria, Santiago de Compostela, Spain 15706; Departments of Cell Biology, Physiology, and Immunology (A.I.-C., E.G.-P., R.M.L., J.P.C.), and Morphological Sciences (L.J.-R.), University of Cordoba, and Reina Sofia University Hospital (P.B., M.A.G.), Maimonides Institute for Research in Biomedicine of Cordoba, Córdoba, Spain 14014; Departments of Endocrinology and Pathology (A.L., M.A.J., A.S., E.V.), Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, University of Sevilla, Sevilla, Spain 41013; Department of Endocrinology (F.J.T.), Hospital Virgen de la Victoria, and Department of Endocrinology (J.A.G.-A.), Hospital Carlos Haya, Malaga, Spain 29010; and CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn) 15706, spain (A.I.-C., F.J.T., P.B., I.B., C.D., R.M.L., J.P.C., C.V.A.), Spain 15706.

Endocrinology
|August 20, 2014
PubMed

Insights

Acromegaly adenomas (ACROs) utilize a RET/Pit1/p14ARF/p53 pathway for apoptosis, which Glial Cell Derived Neurotrophic Factor (GDNF) inhibits. Targeting GDNF

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Oncology

Background:

  • Acromegaly results from somatotroph cell adenomas (ACROs) secreting growth hormone (GH).
  • Rodent studies reveal a RET/Glial Cell Derived Neurotrophic Factor (GDNF) pathway influencing apoptosis via Pit1 and p53.
  • The role of this pathway in human ACROs remains unclear.

Purpose of the Study:

  • To investigate the presence and function of the RET/Pit1/p14ARF/p53/apoptosis pathway in human ACROs compared to nonfunctioning pituitary adenomas (NFPAs).
  • To determine the effect of GDNF on this pathway in ACROs.

Main Methods:

  • Primary cell cultures of human ACROs and NFPAs were treated with and without GDNF.
  • Apoptosis levels were assessed.
  • Protein expression of RET, Pit1, p19Arf, p53, and phospho-Akt was analyzed using Western blotting and qRT-PCR.

Main Results:

  • ACROs, but not NFPAs, exhibited significant apoptosis when deprived of GDNF, which GDNF prevented.
  • This apoptosis was linked to RET processing, Pit1 accumulation, and p14ARF/p53 induction, inhibited by GDNF via phospho-Akt activation.
  • Overexpression of human Pit1 induced apoptosis in a pituitary cell line, and GDNF expression correlated with RET and inversely with p53 in tumors.

Conclusions:

  • Human ACROs possess an active RET/Pit1/p14ARF/p53/apoptosis pathway.
  • GDNF inhibits this pathway, promoting ACRO cell survival.
  • Disrupting GDNF's survival function presents a potential therapeutic strategy for acromegaly.

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