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Osteoblast derived factors induce androgen independent proliferation and expression of prostate specific antige in human prostate cancer cells Blaszczyk, Natalie

Abstract

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). Factors secreted by osteoblasts have been implicated in mediating progression to androgen independence. Here we investigated the possibility that human osteoblasts might secrete factors that contribute to the emergence of androgen independent prostate cancer. 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 a proliferation 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 was investigated by neutralization studies with anti IL-6 antibodies. OCM increased the proliferation and the expression of PSA at both the protein and RNA levels in LNCaP cells. Synergistic increases in the activities of PSA(6.1kb) and pARR₃-tk-luciferase reporters were measured in cells co-treated with both OCM and androgen. OCM targeted the N-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. 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. Therefore, other AR-regulated genes involved in proliferation and regulatory mechanisms may also be activated in the absence of androgens by OCM. This suggests that the AR may play a role in the progression of prostate cancer to androgen independence by a mechanism initiated by factors secreted from the bone, such as IL-6. Identifying such molecular mechanisms may lead to improved clinical management of metastatic prostate cancer, which has a poor prognosis and significant morbidity and mortality.

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