Activation of the parathyroid hormone receptor-adenylate cyclase system in osteosarcoma cells by a human renal...

Human renal carcinoma cell line 786-0 elaborates a protein that is structurally and immunochemically distinct from parathyroid hormone (PTH) and that activates renal cortical adenylate cyclase via an interaction with the PTH receptor. Because of the high frequency of excessive bone resorption and resultant hypercalcemia in patients with malignant disease we evaluated the ability of this 786-0 cell factor to reproduce PTH action in bone-derived cells. The 786-0 factor as well as bovine PTH (BPTH) (1-34) and prostaglandin E1 produced marked increases in cyclic adenosine 3':5'-monophosphate (cAMP) accumulation in the clonal rat osteosarcoma cell line UMR-106. A competitive antagonist of PTH action, [norleucine8, norleucine18, tyrosine34] BPTH(3-34)amide, blocked the cAMP stimulation produced by 786-0 factor and BPTH(1-34) but not that produced by prostaglandin E1. In the presence of forskolin (0.1 microM) UMR-106 cells were extremely sensitive to 786-0 factor, showing significant increases in cAMP production at a concentration 10-fold less than that required to activate adenylate cyclase in renal membranes. In contrast UMR-106 cells were less sensitive to BPTH(1-34) than were renal membranes. This preferential increase in sensitivity to 786-0 factor was not seen in membranes prepared from UMR-106 cells suggesting the importance of cytosolic components. Six additional human genitourinary carcinoma cell lines were found to produce factors that increased cAMP levels in UMR-106 cells. We conclude that 786-0 factor is a potent activator of the PTH receptor-adenylate cyclase system in these bone-derived cells. These findings are consistent with the view that cancer-associated hypercalcemia may frequently be attributable to tumor secretion of proteins (such as 786-0 factor) that are distinct from PTH but are capable of activating skeletal PTH receptors.