Bone morphogenic proteins (BMPs) have been demonstrated to impact tumorigenesis in a variety of tumors. As for the adrenal cortex, BMP6 has been implicated as an important modulator of aldosterone secretion. To screen for alterations of BMP dependent pathways in adrenal tumorigenesis we performed gene profiling experiments. By comparing human adrenal carcinoma (ACC) against normal adrenal glands (Co) we detected a down-regulation of various BMPs (e.g. BMP2, BMP5) which was further validated by qPCR (Co vs ACC, BMP5, 100±29.7 vs 6.1±1.4%; BMP2, 100±17 vs 35.1±1.2%). Similar expression patterns were seen in two human ACC cell lines (NCIh295R, SW13), which were therefore used as an in vitro model for further studies of the impact of BMP on adrenal function. Integrity of the pathway could be demonstrated by incubation with recombinant hBMP2 and 5, which induced phosphorylation of SMAD1/5/8 and subsequent increase of ID protein expression levels in a dose dependent manner. Co-incubation with the physiological BMP antagonist Noggin neutralized these effects. On a functional level, incubation with BMP2 significantly diminished cell proliferation in a dose dependent manner (untreated versus BMP2; 10, 50, 100, 300 ng/ml, 100±8.9 vs 78.9±4.5 vs 66.2±2.3 vs 55.1±4.6%). Moreover, BMP2/5 treatment resulted in a decrease of forskolin stimulated cortisol production (untreated versus BMP2, 151.3±6.3 vs 48.3±1.2 nmol/l; untreated versus BMP5 438.0±31.2 vs 254.3±6.3 nmol/), which was accompanied by down-regulation of 3ßHSD (untreated versus BMP2, 100±14.3 vs 11.2±0.2 vs BMP5, 8.5±0.8) and MC2-R expression (untreated versus BMP2, 100±0.8 vs 17.3±0.5 vs BMP5, 10.8±0.8). Taken together, we demonstrate that loss of BMP expression is a common finding in ACC and we provide evidence that BMP dependent pathways might be involved in modulation of the malignant phenotype of this cancer.
03 - 07 May 2008
European Society of Endocrinology