title: Extracellular calcium as a candidate mediator of prostate cancer skeletal metastasis.
abstract: Prostate cancer almost exclusively metastasizes to skeletal sites, indicating that the bone provides a favorable microenvironment for its localization and progression. A natural yet understudied factor in bone that could facilitate tumor localization is elevated extracellular calcium ([Ca2+]o). The present study found that elevated [Ca2+]o (2.5 mmol/L) enhanced proliferation of skeletal metastatic prostate cell lines (PC-3 and C4-2B), but not the nonskeletal metastatic, epithelial-derived prostate cell line LNCaP. The proliferative effect of elevated [Ca2+]o was associated with higher expression of the calcium-sensing receptor (CaSR), a heterotrimeric G-protein-coupled receptor that is the predominant cell-surface sensor for [Ca2+]o. Knockdown of the CaSR via RNA interference reduced cell proliferation in vitro and metastatic progression in vivo. CaSR signaling in PC-3 cells was evaluated by measuring the elevated [Ca2+]o-dependent inhibition of cyclic AMP accumulation, induced by either prostaglandin E2 or forskolin. Elevated [Ca2+]o stabilized expression of cyclin D1, a protein required for cell cycle transition. Furthermore, elevated [Ca2+]o triggered activation of the Akt signaling pathway and enhanced PC-3 cell attachment. Both pertussis toxin (a G-protein inhibitor) and LY294002 (an inhibitor of Akt signaling) reduced cell attachment. These data suggest that elevated [Ca2+]o following increased bone remodeling could facilitate metastatic localization of prostate cancer via the CaSR and the Akt signaling pathway. Taken together, [Ca2+]o is a candidate mediator of prostate cancer bone metastasis.
authors.affiliation: Department of Periodontics and Oral Medicine, School of Dentistry, and Department of Pathology, Medical School, University of Michigan, Ann Arbor, Michigan 48109-1078, USA.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Liao
authors.forename: Abraham
authors.initials: A
authors.lastname: Schneider
authors.forename: Nabanita S
authors.initials: NS
authors.lastname: Datta
authors.forename: Laurie K
authors.initials: LK
authors.lastname: McCauley
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D019938:Cyclin D1 / Q000096:biosynthesis; D006801:Humans; D008297:Male; D009355:Neomycin / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D044169:Receptors, Calcium-Sensing / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D044169:Receptors, Calcium-Sensing; D019938:Cyclin D1; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt; D009355:Neomycin; D002118:Calcium