Teratocarcinoma-derived growth factor-1 is upregulated in aldosterone-producing adenomas and increases aldosterone secretion and inhibits apoptosis in vitro

Tracy A. Williams, Silvia Monticone, Fulvio Morello, Choong Chin Liew, Giulio Mengozzi, Catia Pilon, Sofia Asioli, Anna Sapino, Franco Veglio, Paolo Mulatero

Research output: Contribution to journalArticle

Abstract

Aldosterone-producing adenomas (APA) are a frequent cause of secondary hypertension characterized by autonomous hypersecretion of aldosterone. However, the molecular mechanisms involved in adrenal tumorigenesis and deregulated aldosterone secretion are currently unknown. To identify putative functional genes, a transcriptional screening was performed on 8 APA and 3 normal adrenals (NA) using oligonucleotide microarrays. Data were next validated on an expanded set of samples by real-time PCR (APA, n=19; NA, n=10). The epidermal growth factor-like teratocarcinoma-derived growth factor-1 (TDGF-1) was upregulated in APA compared with NA (14.7-fold and 21.4-fold by microarray and real-time PCR, respectively). In vitro studies and Western blot analysis using the NCI H295R adrenocortical cell line showed that TDGF-1 increased Akt phosphorylation on Thr308 and Ser473, consistent with activation of phosphatidylinositol 3-kinase/Akt signaling, and also demonstrated a concomitant inactivation of the Akt substrate glycogen synthesis kinase-3β via Ser9 phosphorylation. Furthermore, TDGF-1 mediated a 3.8±0.4-fold increase in aldosterone secretion (n=4) that was specifically blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin (50 nmol/L) and LY294002 (20 μmol/L). Finally, TDGF-1 protected H295R cells from apoptosis induced by staurosporine, causing a decrease in caspase-3 activity, a reduction in the inactivation of poly(ADP-ribose) polymerase, and an inhibition of DNA fragmentation, detected by the TUNEL reaction and fluorescence microscopy that was blocked by LY294002. Taken together, our data suggest that TDGF-1, which is significantly upregulated in APA and mediates aldosterone hypersecretion and deregulated growth in adrenocortical cells in vitro, may represent a key player in the development and pathophysiology of primary aldosteronism.

Original languageEnglish
Pages (from-to)1468-1475
Number of pages8
JournalHypertension
Volume55
Issue number6
DOIs
Publication statusPublished - Jun 2010

Keywords

  • Aldosterone
  • Aldosterone-producing adenoma
  • NCI H295R cells
  • Phosphatidylinositol 3-kinase/Akt signaling
  • Teratocarcinoma-derived growth factor

ASJC Scopus subject areas

  • Internal Medicine

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