Osteoblast-derived factors induce androgen-independent proliferation and expression of prostate-specific antigen in human prostate cancer cells.
OBJECTIVE
Prostate cancer metastasizes to the skeleton to form osteoblastic lesions. Androgen ablation is the current treatment for metastatic prostate cancer. This therapy is palliative, and the disease will return in an androgen-independent form that is preceded by a rising titer of prostate-specific antigen (PSA). Here, we investigated the possibility that human osteoblasts might secrete factors that contribute to the emergence of androgen-independent prostate cancer.


METHODS
Primary cultures of human osteoblasts were used as a source of conditioned medium (OCM). Proliferation, expression of androgen-regulated genes, and transactivation of the androgen receptor (AR) were monitored in LNCaP human prostate cancer cells in response to OCM using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Northern blot analysis, and reporter gene constructs. Levels of interleukin-6 (IL-6) present in OCM were measured, and its contribution to proliferation and expression of PSA were investigated by neutralization studies with anti IL-6 antibodies.


RESULTS
OCM increased the proliferation and expression of PSA at both the protein and RNA levels in LNCaP cells. Synergistic increases in the activities of PSA (6.1 kb)- and pARR(3)-tk-luciferase reporters were measured in cells cotreated with both OCM and androgen. OCM targeted the NH(2)-terminal domain of the AR. The effect of OCM on transcriptional activity of the AR was inhibited by an antiandrogen. Neutralizing antibodies to IL-6 blocked proliferation and expression of PSA by OCM.


CONCLUSIONS
Osteoblasts secrete factors, such as IL-6, that cause androgen-independent induction of PSA gene expression and proliferation of prostate cancer cells by a mechanism that partially relies on the AR. Identifying such molecular mechanisms may lead to improved clinical management of metastatic prostate cancer.
Blaszczyk
Natalie
N
Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Masri
Bassam A
BA
Mawji
Nasrin R
NR
Ueda
Takeshi
T
McAlinden
Gavan
G
Duncan
Clive P
CP
Bruchovsky
Nicholas
N
Schweikert
Hans-Udo
HU
Schnabel
Doris
D
Jones
Edward C
EC
Sadar
Marianne D
MD
D000728:Androgens / Q000502:physiology*; D002455:Cell Division; D045744:Cell Line, Tumor; D017930:Genes, Reporter; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D008297:Male; D010006:Osteoblasts / Q000502:physiology*; D017430:Prostate-Specific Antigen / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection
D000728:Androgens; D015850:Interleukin-6; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D008156:Luciferases; D017430:Prostate-Specific Antigen