The decrease in plasma Pi concentration and in Pi tubular reabsorption that is often encountered in malignant hypercalcemia may be ascribed to a tumor-produced parathyroid hormone (PTH)-related protein. However, tumors are known to synthesize a variety of substances, among which is transforming growth factor-alpha (TGF-alpha). We investigated the effects of TGF-alpha on Na-dependent Pi transport and on the response to PTH-related protein in cultured opossum renal epithelial cells. TGF-alpha caused a concentration- and time-dependent decrease in Na-dependent Pi transport. The inhibition of Na-dependent Pi transport was detectable by 14 h of incubation and maximal by 24 h. At that time, a concentration of 10 ng/ml of TGF-alpha produced a 35 +/- 1% inhibition. This was not associated with any change in prostaglandin production. The adenosine 3',5'-cyclic monophosphate (cAMP) response to PTH-related protein, PTH, prostaglandin E2 or forskolin, but not to pertussis toxin, was diminished in cells treated with TGF-alpha for 24 h. Similar effects on Na-dependent Pi transport and cAMP production were observed in cells incubated with epidermal growth factor. The inhibition of Na-dependent Pi transport induced by either PTH-related protein or PTH was reduced after incubation with TGF-alpha. Thus two different tumoral products, TGF-alpha and PTH-related protein, are each capable of inhibiting Na-dependent Pi transport in cultured renal cells. Both peptides may also interact and influence the effects of each other on renal Pi transport.