Effect of synthetic tumoral PTH-related peptide on cAMP production and Na-dependent Pi transport

Abstract

Malignant hypercalcemia can be associated with a biochemical syndrome very similar to that encountered in primary hyperparathyroidism. The putative tumoral factor responsible for this syndrome has been isolated very recently from conditioned medium of a cultured lung squamous cell carcinoma (BEN), cDNA clones characterized, and an amino-terminal fragment synthesized. We investigated and compared the effect of this synthetic amino-terminal fragment of parathyroid hormone-related peptide [PTHrP-(1-34)], to purified PTHrP-(1-141) isolated from the same lung squamous cell carcinoma, and to bovine parathyroid hormone [bPTH-(1-34)] on adenosine 3',5'-cyclic monophosphate (cAMP) production and sodium-dependent phosphate transport (NaPiT) in opossum kidney (OK) epithelial cells. PTHrP-(1-34) and bPTH-(1-34) were equipotent in eliciting a 30-fold increase of cAMP production. NaPiT, as assessed by measuring the initial rate of Pi uptake, was inhibited in a concentration-dependent manner by either synthetic peptide. Half-maximal inhibition was observed with approximately 0.03-0.1 nmol/l of either bPTH-(1-34) or PTHrP-(1-34). At 10 nmol/l, either peptide produced an inhibition of 55 +/- 4 and 53 +/- 6%, respectively. This effect was specific for Pi, since the Na-dependent transport of glucose or alanine was not altered by either peptide. In OK cells dose-dependent stimulation of cAMP production and inhibition of NaPiT were also observed with purified native PTHrP-(1-141). In LLC-PK1 cells, which are devoid of PTH receptors, none of the peptides affected NaPiT. These results demonstrate a direct and specific effect of tumoral PTHrP on cAMP production and NaPiT in cultured renal epithelial cells in a way similar to bPTH.(ABSTRACT TRUNCATED AT 250 WORDS)