Endocrine Abstracts

Members of the TGFb family of ligands - including bone morphogenic proteins (BMPs) - have been demonstrated to profoundly impact tumorigenesis in a variety of tumor entities. As for the adrenal cortex, BMP6 has been implicated as an important modulator of aldosterone secretion. To screen for alterations of TGFß dependent pathways in adrenal tumorigenesis we performed gene profiling experiments. By comparing human adrenal carcinoma (ACC) against normal adrenal tissue samples (Co) we detected a down-regulation of various BMPs (e.g. BMP2 and BMP5) which was further validated by Real Time analysis (BMP5, ACC vs. Co 6.1±1.4% vs. 100±29.7%, P<0.01; BMP2, ACC vs. Co 35.1±1.2% vs. 100±17%, P<0.01). As similar expression pattern with loss of BMP5 expression was evident in NCIh295 cells, this cell line was used as an in vitro model to assess potential impact of BMP dependent pathways. Incubation with recombinant hBMP5 induced phosphorylation of SMAD 1/5/8 and subsequent increase of ID protein expression levels in a dose dependent manner, while co-incubation with the physiological BMP antagonist Noggin neutralized these effects. Thus, these findings demonstrated the integrity of the pathway in NCIh295 cells. Notably, BMP5 treatment resulted in a decrease in cellular viability (68.3±1.1% vs. 100±2.7%, P<0.01) but increase in the expression levels of steroidogenic enzymes such as StAR (225±9.6% vs. 100±2.3%, P<0.01) and SCC (460.3±58.8% vs. 100±0.53%, P<0.01). The BMP5 dependent reduced viability was accompanied by concomitant changes in the cell cycle possibly through an increased rate in apoptosis. Taken together, we demonstrate that loss of BMP expression is a common finding in ACC. Moreover, we provide first evidence that BMP dependent pathways might be involved in modulation of the malignant phenotype of adrenocortical cancer.