Bone morphogenetic proteins 2 and 5 are down-regulated in adrenocortical carcinoma and modulate adrenal cell proliferation and steroidogenesis.
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.
Johnsen
Inga K
IK
Departments of Medicine, University Hospital Innenstadt, Ludwig Maximilians University, Munich, Germany.
Kappler
Roland
R
Auernhammer
Christoph J
CJ
Beuschlein
Felix
F
D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000450:Aldosterone / Q000378:metabolism; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D055417:Bone Morphogenetic Protein 5 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D055396:Bone Morphogenetic Protein 2; D055417:Bone Morphogenetic Protein 5; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D011994:Recombinant Proteins; D005576:Colforsin; D000450:Aldosterone; D014212:Tretinoin; D007334:Insulin-Like Growth Factor I; D013254:Steroid 17-alpha-Hydroxylase; D051057:Proto-Oncogene Proteins c-akt; D052004:Bone Morphogenetic Protein Receptors; D006854:Hydrocortisone