title: Expression profile of WNT molecules in prostate cancer and its regulation by aminobisphosphonates.
abstract: Skeletal metastases represent a frequent complication in patients with advanced prostate cancer (PCa) and often require bisphosphonate treatment to limit skeletal-related events. Metastasized PCa cells disturb bone remodeling. Since the WNT signaling pathway regulates bone remodeling and has been implicated in tumor progression and osteomimicry, we analyzed the WNT profile of primary PCa tissues and PCa cell lines and assessed its regulation by bisphosphonates. Prostate tissue (n = 18) was obtained from patients with benign prostate hyperplasia (BPH) and PCa patients with different disease stages. Serum samples were collected from 62 patients. Skeletal metastases were present in 17 patients of whom 6 had been treated with zoledronic acid. The WNT profile and its regulation by bisphoshonates were analyzed in tissue RNA extracts and serum samples as well as in osteotropic (PC3) and non-osteotropic (DU145, LNCaP) PCa cell lines. Several members of the WNT pathway, including WNT5A, FZD5, and DKK1 were highly up-regulated in PCa tissue from patients with advanced PCa. Interestingly, osteotropic cells showed a distinct WNT profile compared to non-osteotropic cells. While WNT5A, FZD5, and DKK1 were highly expressed in PC3 cells, WNT1 and SFRP1 mRNA levels were higher in DU145 cells. Moreover, zoledronic acid down-regulated mRNA levels of WNT5A (-34%), FZD5 (-60%), and DKK1 (-46%) in PC3 cells. Interestingly, patients with skeletal metastases who received zoledronic acid had twofold higher DKK1 serum levels compared to bisphosphonate-naive patients. The WNT signaling pathway is up-regulated in advanced PCa, differentially expressed in osteotropic versus non-osteotropic cells, and is regulated by zoledronic acid.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolic Bone Diseases, Department of Medicine III, Technical University, Dresden, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Thiele
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.forename: Claudia
authors.initials: C
authors.lastname: Goettsch
authors.forename: Tilman D
authors.initials: TD
authors.lastname: Rachner
authors.forename: Peggy
authors.initials: P
authors.lastname: Benad
authors.forename: Susanne
authors.initials: S
authors.lastname: Fuessel
authors.forename: Kati
authors.initials: K
authors.lastname: Erdmann
authors.forename: Christine
authors.initials: C
authors.lastname: Hamann
authors.forename: Gustavo B
authors.initials: GB
authors.lastname: Baretton
authors.forename: Manfred P
authors.initials: MP
authors.lastname: Wirth
authors.forename: Franz
authors.initials: F
authors.lastname: Jakob
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
mesh_terms: D000368:Aged; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism; D060528:Wnt4 Protein; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; C501126:DKK1 protein, human; D004164:Diphosphonates; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; C495247:WNT1 protein, human; C491119:WNT10B protein, human; C555581:WNT4 protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051155:Wnt1 Protein; D060528:Wnt4 Protein; D000077211:Zoledronic Acid