Parathyroid hormone-related protein enhances PC-3 prostate cancer cell growth via both autocrine/paracrine and intracrine pathways.
Parathyroid hormone-related protein (PTHrP) is expressed by human prostatic tissue and prostate cancer cell lines, and positively influences primary prostate tumor growth in vivo. The human prostate cancer cell line PC-3, which expresses functional PTH/PTHrP receptors, was used as a model to study the effects of PTHrP on prostate cancer cell growth. Addition of PTHrP (1-34), (1-86), and (1-139) increased cell number and [3H]thymidine incorporation; these effects were reversed by anti-PTHrP antiserum. This antiserum also decreased endogenous PC-3 cell growth. Clonal PTHrP-overexpressing PC-3 cell lines also showed enhanced cell growth and [3H]thymidine incorporation and were enriched in the G2+M phase of the cell cycle, suggesting an effect of PTHrP on mitosis. Overexpression of PTHrP with the nuclear localization sequence (NLS) deletion partially reversed the growth-stimulatory effects. The growth rate of these cells was midway between that of wild-type PTHrP-overexpressing and control cells, presumably because NLS-mutated PTHrP is still secreted and acts through the cell surface PTH/PTHrP receptor. In contrast to NLS-mutated PTHrP, wild-type protein showed preferential nuclear localization. These results suggest that the proliferative effects of PTHrP in PC-3 cells are mediated via both autocrine/paracrine and intracrine pathways, and that controlling PTHrP production in prostate cancer may be therapeutically beneficial.
Tovar Sepulveda
Veronica A
VA
Department of Pharmacology and Toxicology, University of Texas Medical Branch, 10th and Market Streets, Galveston, TX 77555, USA.
Falzon
Miriam
M
D019898:Autocrine Communication / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D016195:G2 Phase; D006801:Humans; D008297:Male; D008938:Mitosis; D009500:Neutralization Tests; D019913:Nuclear Localization Signals / Q000378:metabolism*; D019899:Paracrine Communication / Q000502:physiology*; D010281:Parathyroid Hormone / Q000235:genetics; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D011471:Prostatic Neoplasms; D011506:Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D019913:Nuclear Localization Signals; C470121:PTHLH protein, human; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D010455:Peptides; D011506:Proteins; C085849:parathyroid hormone-related protein (1-16); C068871:parathyroid hormone-related protein (1-86); C054296:parathyroid hormone-related protein (1-34); C071097:parathyroid hormone-related protein (107-139)