An androgen-IL-6-Stat3 autocrine loop re-routes EGF signal in prostate cancer cells.
Abstract
Dynamic modulation of information flow within signaling networks allows the cell to respond to micro-environmental changes. This property of the cell, while being essential to survival and eliciting appropriate responses, can also be detrimental to the organism by allowing cancerous cells to evade regulation and proliferate. We determined if changes in expression levels of transcriptional regulators and their interactions could alter routing within signaling networks in prostate cancer cells. Increasing the protein levels of the signal transducer and activator of transcription 3 (Stat3) led to Stat3-androgen receptor (AR) complex formation in response to epidermal growth factor (EGF) and interleukin-6 (IL-6) stimulation. Increasing the protein levels of Stat3 increased the EGF induced transcriptional activation of the androgen receptor. Androgen pre-treatment increased Stat3 protein levels in an IL-6 autocrine/paracrine dependent manner in the cells suggesting a feedback loop within cells. Increased Stat3-AR complex leads to a change in the routing of the epidermal growth factor signal allowing the androgen receptor to become activated in a Stat3 dependent manner. Understanding interactions and changes in signal flow within the cell is important to our understanding of signaling networks as well as our ability to identify cellular targets for novel therapies to inhibit cancer progression.
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STAT3 interacts directly with amino acids 234-558 of the AR, and this interaction is dependent upon phosphorylation of STAT3 at Ser-722.
“STAT3 interacts directly with amino acids 234 -558 of the AR (23), an interaction that is dependent upon phosphorylation of STAT3 at Ser-722 (24).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [24]
EGF can induce IL-6 up-regulation in prostate cancer cells.
“EGF can also induce IL-6 up-regulation in prostate cancer cells (24).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [24]
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- Authors
- Aaronson, D. S., Muller, M., Neves, S. R., Chung, W.-C., Jayaram, G., Iyengar, R., & Ram, P. T.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Ram, Prahlad T.
- Venue
- Molecular and Cellular Endocrinology
- Publisher
- Elsevier BV
- Published
- 2007-05
- Volume
- 270
- Issue
- 1-2
- Pages
- 50-56
- ISSN
- 0303-7207 (ISSN-L)
- OpenAlex
- W2006278935
- Cited by
- 47
- References
- 26
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 4 · 2015: 3 · 2014: 3 · 2013: 5 · 2012: 5
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Molecular and Cellular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- prostate cancer, androgen receptor, STAT3, interleukin-6, epidermal growth factor, autocrine signaling, transcriptional activation, feedback loops, tumor progression
- MeSH terms
- Epidermal Growth Factor, Humans, Male, Prostatic Neoplasms, Receptors, Androgen, RNA, Messenger, Signal Transduction, Metribolone, Interleukin-6, Gene Expression Regulation, Neoplastic, Autocrine Communication, Feedback, Physiological, STAT3 Transcription Factor
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