Bone morphogenetic proteins 2 and 5 are down-regulated in adrenocortical carcinoma and modulate adrenal cell proliferation and steroidogenesis

Cancer Res. 2009 Jul 15;69(14):5784-92. doi: 10.1158/0008-5472.CAN-08-4428. Epub 2009 Jul 7.

Abstract

Bone morphogenetic proteins (BMP) have been shown to affect tumorigenesis in a variety of tumors. Quantitative PCR analysis revealed down-regulation of BMP2 and BMP5 in tissue samples from adrenocortical carcinoma and adrenocortical tumor cell lines compared with normal adrenal glands. Integrity of BMP-dependent pathways in these cell lines could be shown by activation of the Smad1/5/8 pathway with subsequent increase of ID protein expression upon incubation with BMP2 or BMP5. On a functional level, BMP treatment resulted in inhibition of cell proliferation and viability in a dose- and time-dependent manner. This growth inhibitory effect was associated with BMP-dependent reduction of AKT phosphorylation under baseline conditions and under insulin-like growth factor costimulation. Furthermore, steroidogenic function, including melanocortin-2 receptor and steroidogenic enzyme expressions, was profoundly reduced. In vitro demethylation treatment and overexpression of GATA6 resulted in reactivation of BMP-dependent pathways with concomitant modulation of steroidogenesis. Taken together, we show that loss of expression of members of the BMP family of ligands is a common finding in adrenocortical tumors and we provide evidence that BMP-dependent pathways are likely to be involved in the modulation of the malignant and functional phenotype of adrenocortical cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Neoplasms / genetics*
  • Adrenal Cortex Neoplasms / metabolism
  • Adrenal Cortex Neoplasms / pathology
  • Adrenocortical Carcinoma / genetics*
  • Adrenocortical Carcinoma / metabolism
  • Adrenocortical Carcinoma / pathology
  • Aldosterone / metabolism
  • Blotting, Western
  • Bone Morphogenetic Protein 2 / genetics*
  • Bone Morphogenetic Protein 2 / metabolism
  • Bone Morphogenetic Protein 2 / pharmacology
  • Bone Morphogenetic Protein 5 / genetics*
  • Bone Morphogenetic Protein 5 / metabolism
  • Bone Morphogenetic Protein 5 / pharmacology
  • Bone Morphogenetic Protein Receptors / genetics
  • Bone Morphogenetic Protein Receptors / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Colforsin / pharmacology
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • GATA6 Transcription Factor / genetics
  • GATA6 Transcription Factor / metabolism
  • Humans
  • Hydrocortisone / metabolism
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / pharmacology
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Recombinant Proteins / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Steroid 17-alpha-Hydroxylase / genetics
  • Steroid 17-alpha-Hydroxylase / metabolism
  • Time Factors
  • Tretinoin / pharmacology
  • Tumor Cells, Cultured

Substances

  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 5
  • GATA6 Transcription Factor
  • GATA6 protein, human
  • Recombinant Proteins
  • Colforsin
  • Aldosterone
  • Tretinoin
  • Insulin-Like Growth Factor I
  • Steroid 17-alpha-Hydroxylase
  • Proto-Oncogene Proteins c-akt
  • Bone Morphogenetic Protein Receptors
  • Hydrocortisone