Proliferative effect of parathyroid hormone-related protein on the hypercalcemic Walker 256 carcinoma cell line.

The rat Walker 256 carcinoma is an animal model for humoral hypercalcemia of malignancy. This tumor produces and secretes parathyroid hormone (PTH)-related protein (PTHrP), a likely mediator for this syndrome. In this study, we investigated the effect of PTHrP on Walker 256 tumor cell proliferation. We found that [Tyr36]human (h)PTHrP (1-36)NH2 and hPTHrP (1-86), unlike hPTHrP (38-64)NH2, stimulate DNA synthesis dose-dependently in these cells. A similar mitogenic effect was also observed with bovine (b)PTH (1-34) or (Nle8.18, Tyr34)bPTH (3-34)NH2. Moreover, addition of anti-hPTHrP (1-34) neutralizing antibodies decreased tumor cell growth. Conversely, 10(-4)M dibutyryl cAMP or Sp-cDBIMPS (a cAMP analogue) inhibited DNA synthesis in these cells, being incompetent at lower doses. PTHrP or PTH failed to stimulate cAMP production, but they induced a cytosolic calcium transient increase in these cells. These findings support an autocrine role of PTHrP in the regulation of this tumor growth.