Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor.
Open accessAbstract
It is hypothesized that ligand-independent activation of the androgen receptor is one of the mechanisms implicated in tumour progression. However, supportive evidence is limited to the effect of HER-2/neu that stimulates prostate cancer progression through activation of the androgen receptor. In the present study, we have asked whether the proinflammatory cytokine interleukin-6 (IL-6), which is known to stimulate androgen receptor activity and expression of its downstream target genes, may also induce growth of androgen-sensitive cells. We have found that IL-6 differentially regulates proliferation of LAPC-4 and MDA PCa 2b cells. In MDA PCa 2b cells, growth stimulation by IL-6 was reversed by administration of either the non-steroidal anti-androgen bicalutamide or the inhibitor of the mitogen-activated protein kinase pathway PD98059. Neither cell line was found to express endogenous IL-6. Interestingly, the treatment of those prostate cancer cells did not increase phosphorylation of STAT3. The effect of IL-6 on stimulation of androgen receptor activity in MDA PCa 2b cells was lower than that of androgen, comparable with findings reported by other researchers. However, growth of MDA PCa 2b xenografts in castrated animals treated with IL-6 was similar to that in non-castrated animals. In addition, bicalutamide showed an inhibitory effect on IL-6-regulated growth in vivo. Taken together, data in the present study demonstrate that IL-6 may cause growth of androgen receptor-positive tumours in vitro and in vivo through activation of the androgen receptor.
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IL-6 via STAT-3 promotes tumor cell proliferation in many cancers, including oral squamous cell carcinoma via DNA hypomethylation, prostate cancer through androgen receptor activation, and colon cancer.
“IL-6 via STAT-3 has been shown to promote tumor cell proliferation in many cancers, including oral squamous cell carcinoma via DNA hypomethylation (31), prostate cancer through androgen receptor activation (32), and colon cancer (33).”
From Tumor-Induced Inflammatory Cytokines and the Emerging Diagnostic Devices for Cancer Detection and Prognosis (2021) · cites this paper as [32]
The Discussion reports IL-6-stimulated growth and androgen-receptor activation in MDA PCa 2b prostate cancer cells. But its signalling table and the section on STAT3 phosphorylation report no IL-6-induced STAT3 phosphorylation in those cells, so the cited study does not support the claim that this growth occurs via STAT3. This citation is attached to the prostate-cancer example, not the oral or colon cancer examples. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIL-6 treatment is agonistic for AR activity in LAPC-4 cells expressing wild-type AR and in MDA-PCa-2b cells expressing double-mutant AR (L701H and T877A), whereas IL-6 inhibits ligand-independent AR activity in T877A AR-expressing LNCaP cells.
“The effect of IL-6 treatment on LAPC-4 cells, which express a wild-type AR and in MDA-PCa-2b cells, which express a double-mutant AR (substitutions at L701H and T877A) is agonistic, whereas IL-6 inhibits ligand-independent AR activity in T877A ARexpressing LNCaP cells (20).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [20]
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Flagged first, then by citations
Research works printed but not linked: 3
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Sorted by citations
Kartikasari, A. E. R., Huertas, C. S., Mitchell, A., & Plebanski, M. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.692142 · Cited by 343 · see citing works
“IL-6 via STAT-3 has been shown to promote tumor cell proliferation in many cancers, including oral squamous cell carcinoma via DNA hypomethylation (31), prostate cancer through androgen receptor activation (32), and colon cancer (33).”
BackgroundAndrogen receptor signaling in prostate cancer
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Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer
Lamont, K. R., & Tindall, D. J. (2011) · Molecular Endocrinology · doi:10.1210/me.2010-0469 · Cited by 150 · see citing works
- Authors
- Malinowska, K., Neuwirt, H., Cavarretta, I. T., Bektic, J., Steiner, H., Dietrich, H., Moser, P. L., Fuchs, D., Hobisch, A., & Culig, Z.
- Affiliations
- Innsbruck Medical University (AT)
- Landeskrankenhaus Feldkirch (AT)
- Venue
- Endocrine Related Cancer
- Publisher
- Bioscientifica
- Published
- 2009-03
- Volume
- 16
- Issue
- 1
- Pages
- 155-169
- ISSN
- 1351-0088 (ISSN-L)
- 1479-6821
- OpenAlex
- W2170874144
- Cited by
- 157
- References
- 66
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 11 · 2020: 8 · 2019: 4 · 2018: 7 · 2017: 9 · 2016: 14 · 2015: 8 · 2014: 11 · 2013: 17 · 2012: 13
- FWCI
- 13.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrine Related Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission
- Austrian Science Fund
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- interleukin-6, prostate cancer, androgen receptor, ligand-independent receptor activation, tumor growth, bicalutamide, androgen receptor antagonists, MAPK signaling, PD98059, STAT3, LAPC4 cells, xenografts, castration, inflammatory cytokines
- MeSH terms
- Anilides, Animals, Antineoplastic Agents, Cell Division, Humans, Male, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Nitriles, Orchiectomy, Phosphorylation, Prostatic Neoplasms, Receptors, Androgen, RNA, Messenger, Tosyl Compounds, Signal Transduction, Interleukin-6, Receptors, Interleukin-6, Mitogen-Activated Protein Kinases, Cell Line, Tumor, STAT3 Transcription Factor, Mice, In Vitro Techniques
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