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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenal Cortex Neoplasms / genetics*
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Adrenal Cortex Neoplasms / metabolism
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Adrenal Cortex Neoplasms / pathology
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Adrenocortical Carcinoma / genetics*
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Adrenocortical Carcinoma / metabolism
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Adrenocortical Carcinoma / pathology
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Aldosterone / metabolism
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Blotting, Western
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Bone Morphogenetic Protein 2 / genetics*
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Bone Morphogenetic Protein 2 / metabolism
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Bone Morphogenetic Protein 2 / pharmacology
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Bone Morphogenetic Protein 5 / genetics*
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Bone Morphogenetic Protein 5 / metabolism
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Bone Morphogenetic Protein 5 / pharmacology
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Bone Morphogenetic Protein Receptors / genetics
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Bone Morphogenetic Protein Receptors / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Colforsin / pharmacology
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Dose-Response Relationship, Drug
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Down-Regulation / drug effects
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GATA6 Transcription Factor / genetics
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GATA6 Transcription Factor / metabolism
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Humans
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Hydrocortisone / metabolism
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Insulin-Like Growth Factor I / genetics
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Insulin-Like Growth Factor I / pharmacology
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Recombinant Proteins / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Steroid 17-alpha-Hydroxylase / genetics
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Steroid 17-alpha-Hydroxylase / metabolism
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Time Factors
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Tretinoin / pharmacology
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Tumor Cells, Cultured
Substances
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Protein 5
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GATA6 Transcription Factor
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GATA6 protein, human
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Recombinant Proteins
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Colforsin
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Aldosterone
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Tretinoin
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Insulin-Like Growth Factor I
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Steroid 17-alpha-Hydroxylase
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Proto-Oncogene Proteins c-akt
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Bone Morphogenetic Protein Receptors
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Hydrocortisone