title: Local secretion of parathyroid hormone-related protein by an osteoblastic osteosarcoma (UMR 106-01) cell line results in growth inhibition.
abstract: Parathyroid hormone-related protein (PTHrP) has been implicated as being important in the growth of tumor cells responsive to the peptide. We utilized a rat osteoblastic osteosarcoma cell line, UMR 106-01, which has PTHrP receptors and a PTHrP-responsive adenylate cyclase/cAMP messenger system, to produce a modified cell line that overexpresses PTHrP. The human PTHrP cDNA sequence was transfected by electroporation into UMR 106-01 cells and the stable cell lines UMR-36 and UMR-34 were established. The modified cell line, UMR-36, had increased levels of PTHrP mRNA compared with control cell lines and secreted PTHrP into the culture medium at levels of 0.01-0.1 pmol/10(7) cells in 12 h. The secreted peptide was biologically active as indicated by its ability to activate adenylate cyclase. The number of UMR-36 cells following 9 days in culture was reduced by up to 80% compared with control lines, which was associated with decreased (3)H-thymidine incorporation into genomic DNA. Addition of 1000-fold excess of the PTHrP antagonist, PTHrP(7-34), to UMR-36 cells resulted in the escape of growth inhibition and increased rate of growth. In vivo, tumors derived from UMR-36 cells were smaller in size compared with tumors derived from control cells. In conclusion, increased autocrine secretion of, and responsiveness to, PTHrP results in inhibited growth kinetics of an osteoblast-like bone tumor cell line in vitro and in vivo.
authors.affiliation: Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Victoria, Australia.
authors.forename: G M F
authors.initials: GM
authors.lastname: Pasquini
authors.forename: R A M
authors.initials: RA
authors.lastname: Davey
authors.forename: P W M
authors.initials: PW
authors.lastname: Ho
authors.forename: V P
authors.initials: VP
authors.lastname: Michelangeli
authors.forename: V
authors.initials: V
authors.lastname: Grill
authors.forename: S J
authors.initials: SJ
authors.lastname: Kaczmarczyk
authors.forename: J D
authors.initials: JD
authors.lastname: Zajac
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010006:Osteoblasts / Q000378:metabolism*; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D006131:Growth Inhibitors; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones