Parathyroid hormone-related protein purified from a human lung cancer cell line.

Abstract

A protein with biological activities similar to parathyroid hormone (PTH) has been purified from serum-free culture medium obtained from a human lung cancer cell line (BEN). A major protein band of 18 kDa was obtained on NaDodSO4/polyacrylamide gels, with faint bands at 35 kDa and 67 kDa. Biological activity was associated only with the 18-kDa band. Amino acid sequence analysis of the material purified by HPLC revealed that 8 of the 16 residues were identical with those of human PTH. Antibody raised to a corresponding synthetic peptide recognized the PTH-related material but showed <1% cross-reactivity with human PTH amino-terminal peptides. BEN cells contained PTH DNA, but not PTH messenger RNA, indicating involvement of another gene. The purified PTH-related protein had a specific biological activity %-6 times greater than that of bovine PTH(1-34). The PTH-related protein may have a role in the syndrome of humoral hypercalcemia of malignancy.Humoral hypercalcemia of malignancy (HHM) is a very common complication of certain cancers, especially squamous cell carcinoma of the lung, in which it contributes substantially to morbidity and mortality (1). Cancer-derived humoral factors can elevate blood calcium levels by promoting bone resorption and restricting calcium excretion by the kidney (1, 2). Although it was initially thought that "ectopic" production of parathyroid hormone (PTH) by these cancers was the cause of the HHM syndrome, it has become apparent that factors other than PTH are responsible (1-5), including transforming growth factors, which are potent promoters of bone resorption (2, 6). In addition, certain cancers produce a factor that is immunologically distinct from PTH but that resembles PTH in its biological activity. These include tumors from patients with HHM (7,8) and from animal models of HHM (8) and renal cortical carcinoma cells in culture (9).We have found that the BEN cell line, established from a hypercalcemic patient with a squamous cell carcinoma of the bronchus (10), produces appreciable amounts of this PTHlike activity, which stimulates adenylate cyclase in osteoblast-like cells. We report here its purification from BEN cell culture medium and partial structural analysis, revealing the existence of a gene related to the PTH gene.

Parathyroid hormone-related protein in teleost fish

“…Parathyroid hormone-related protein (PTHrP) was dis covered in 1987 in humans as the circulating peptide responsible for the syndrome of humoral hypercalcemia of malignancy (HHM; Moseley et al, 1987). PTHrP and parathyroid hormone (PTH), the main hypercalcemic hor mone in vertebrates, evolved from a common, ancestral gene.…”

Immunochemical Detection of Parathyroid Hormone-Related Protein in the Saccus Vasculosus of a Teleost Fish

“…Parathyroid hormone-related protein was first identified as the mediating factor responsible for hypercalcemia associated with certain human malignant tumors (humoral hypercalcemia of malignancy, HHM), (Moseley et al, 1987). Immunodetectable PTHrP is present in a variety of tumors, especially those of squamous cell origin (Danks et al, 1989); however, it is also found in a range of normal cells, particularly human keratinocytes (Danks et al, 1989).…”

PTHrP Produced by Myeloma Plasma Cells Regulates Their Survival and Pro-Osteoclast Activity For Bone Disease Progression

“…Furthermore, by using rabbit anti-mid-region PTHrP, we specifically revealed a single band of approximately 7 kDa related to the mid-region, as described for other tumors. (9)(10)(11)(23)(24)(25) We also measured RNA levels of both PTHrP and PTH-R1 (Fig. 1D) in selected plasma cell samples, based on the highest cytometric expression.…”

“…(7,8) PTHrP has been primarily reported in patients with osteotropic malignancies, such as breast, lung, and renal cancers, who show skeletal disease and hypercalcemia. (9)(10)(11)(12) Subsequent studies have described its functional effects through either paracrine or autocrine cell stimulation by tumors with no skeleton involvement and even by several normal tissues. (13)(14)(15) An intracrine effect of PTHrP has been also postulated in breast cancer to improve the nucleocytoplasmic trafficking that accelerates cell cycle progression, RNA transcription, and transport.…”