Osteoblast-Derived Factors Induce Androgen-Independent Proliferation and Expression of Prostate-Specific Antigen in Human Prostate Cancer Cells
| Autor: | Edward C. Jones, Gavan McAlinden, Marianne D. Sadar, Hans-Udo Schweikert, Natalie Blaszczyk, Doris Schnabel, Takeshi Ueda, Nicholas Bruchovsky, Clive P. Duncan, Bassam A. Masri, Nasrin R. Mawji |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty medicine.drug_class Biology Transfection urologic and male genital diseases Prostate cancer Genes Reporter Prostate Cell Line Tumor Internal medicine LNCaP medicine Humans Northern blot Luciferases Osteoblasts Interleukin-6 Prostatic Neoplasms Prostate-Specific Antigen medicine.disease Androgen Recombinant Proteins Androgen receptor Prostate-specific antigen Endocrinology medicine.anatomical_structure Oncology Receptors Androgen Cancer cell Androgens Cancer research Cell Division |
| Zdroj: | Clinical Cancer Research. 10:1860-1869 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-0974-3 |
| Popis: | Purpose: 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. Experimental Design: 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 pARR3-tk-luciferase reporters were measured in cells cotreated with both OCM and androgen. OCM targeted the NH2-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. Conclusion: 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|