Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth

Regions of hypoxia are a common feature of solid tumours, When tumour cells are exposed to hypoxic stress, transcription of a battery of genes is init iated. The angiogenic factor adrenomedullin (ADM) is a hypoxia regulated ge ne, ADM is thought to act through the G protein-coupled receptor calcitonin receptor-like receptor (CRLR), with specificity being conferred by the rec eptor associated modifying protein 2 (RAMP2), Here we report for the! first time that ADM treated or stably transfected Ishikawa cells overexpressing ADM show increased resistance to hypoxia induced apoptosis, These cells als o show an upregulation of the oncoprotein Bcl-2, which is protective agains t hypoxic cell death when transiently transfected into Ishikawa cells. Sinc e Ishikawa cells express the putative ADM-receptor CRLR-RAMP2 the productio n and secretion of ADM with the consecutive upregulation of Bcl-2 could est ablish an autocrine/paracrine mechanism rescuing malignant cells from hypox ic cell death. These results, taken together with our previous findings tha t ADM is an angiogenic factor which is upregulated by the nonsteroidal anti estrogen tamoxifen (TAM) in endometrial cells, implicate this peptide as a promoter of tumour growth and a possible target for anticancer strategies. Oncogene (2001) 20, 2937-2945.