Osteoblast-derived factors induce androgen-independent proliferation and expression of prostate-specific antigen in human prostate cancer cells.
Abstract
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 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. 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.
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IL-6 predominantly stimulates Janus kinase signaling and activation of STAT proteins, especially STAT3; MAPK and phosphatidylinositol-3 kinase activation can also occur depending on context.
“The predominant effect of IL-6 in many cell types is the stimulation of Janus kinase (JAK) signaling and activation of signal transducers and activators of transcription (STAT) proteins, especially STAT3; however, activation of MAPK and phosphatidylinositol-3 kinase (PI3K) can also occur depending on the context (13)(14)(15).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [13]
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References 56 · Cited by 66
- Authors
- Blaszczyk, N., Masri, B. A., Mawji, N. R., Ueda, T., McAlinden, G., Duncan, C. P., Bruchovsky, N., Schweikert, H.-U., Schnabel, D., Jones, E. C., & Sadar, M. D.
- Affiliations
- BC Cancer Agency (CA)
- Vancouver General Hospital (CA)
- 4Orthopaedic Surgery, Vancouver General Hospital, British Columbia, Canada
- University of Bonn (DE)
- 3Anatomical Pathology and
- Venue
- Clinical Cancer Research
- Published
- 2004-03-01
- Volume
- 10
- Issue
- 5
- Pages
- 1860-1869
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2138120234
- Cited by
- 66
- References
- 56
- Citations by year
- 2023: 3 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 4 · 2015: 4 · 2014: 4 · 2013: 5 · 2012: 3
- FWCI
- 5.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p50dk047656-07)
- National Institute of Diabetes and Digestive and Kidney Diseases (P50 DK47656)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Oncology › Bone health and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
- Keywords
- castration-resistant prostate cancer, prostate-specific antigen, androgen receptor, interleukin-6, osteoblastic bone metastasis, LNCaP cells, prostate cancer cell proliferation, androgen receptor transactivation, androgen receptor antagonists, conditioned medium
- MeSH terms
- Androgens, Cell Division, Humans, Luciferases, Male, Osteoblasts, Prostatic Neoplasms, Receptors, Androgen, Recombinant Proteins, Transfection, Interleukin-6, Prostate-Specific Antigen, Genes, Reporter, Cell Line, Tumor
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