title: p65-Dependent production of interleukin-1β by osteolytic prostate cancer cells causes an induction of chemokine expression in osteoblasts.
abstract: Skeletal metastases are a frequent complication of prostate, breast and lung cancer, and the interactions of tumor cells with bone-forming osteoblasts and bone-resorbing osteoclasts have been suggested to play critical roles in disease progression. We have previously shown that treatment of primary murine osteoblasts with conditioned medium of the human osteolytic prostate cancer cell line PC-3 results in a rapid induction of chemokine expression, thereby providing further evidence for a molecular crosstalk between bone and tumor cells. The aim of our current study was to identify PC-3-derived molecules mediating this effect. Using Affymetrix Gene Chip hybridization followed by qRT-PCR we were able to confirm that the expression of chemokine-encoding genes is markedly induced in human primary osteoblasts following incubation with PC-3-conditioned medium. Since this induction was significantly affected upon alteration of p65-levels in PC-3 cells, we performed a second genome-wide expression analysis to identify p65-regulated cytokines, which were then tested for their ability to induce chemokine expression. Here we observed that interleukin-1β (IL-1B) did not only increase the expression of chemokines in osteoblasts, but also the phosphorylation of p65 and thereby its own expression. Since immunohistochemistry on bone biopsy sections from prostate cancer metastases demonstrated IL-1B expression in both, tumor cells and osteoblasts, our data suggest that IL-1B is one of the relevant cytokines involved in the skeletal complications of cancer metastases.
authors: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors: Jochen
authors: J
authors: Schulze
authors: Kristoffer
authors: K
authors: Weber
authors: Anke
authors: A
authors: Baranowsky
authors: Thomas
authors: T
authors: Streichert
authors: Tobias
authors: T
authors: Lange
authors: Alexander Simon
authors: AS
authors: Spiro
authors: Joachim
authors: J
authors: Albers
authors: Sebastian
authors: S
authors: Seitz
authors: Josef
authors: J
authors: Zustin
authors: Michael
authors: M
authors: Amling
authors: Boris
authors: B
authors: Fehse
authors: Thorsten
authors: T
authors: Schinke
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000276:immunology / Q000378:metabolism*; D019899:Paracrine Communication; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D018925:Chemokines; D017077:Culture Media, Conditioned; D053583:Interleukin-1beta; C498143:RELA protein, human; D051996:Transcription Factor RelA