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Updated: Jul 1, 2025
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Single-cell deconvolution algorithms analysis unveils autocrine IL11-mediated resistance to docetaxel in prostate
Bisheng Cheng1,2, Lingfeng Li1, Tianlong Luo1
1Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Background:
Docetaxel resistance represents a significant obstacle in the treatment of prostate cancer. The intricate interplay between cytokine signalling pathways and transcriptional control mechanisms in cancer cells contributes to chemotherapeutic resistance, yet the underlying molecular determinants remain only partially understood. This study elucidated a novel resistance mechanism mediated by the autocrine interaction of interleukin-11 (IL-11) and its receptor interleukin-11 receptor subunit alpha(IL-11RA), culminating in activation of the JAK1/STAT4 signalling axis and subsequent transcriptional upregulation of the oncogene c-MYC.
Methods:
Single-cell secretion profiling of prostate cancer organoid was analyzed to determine cytokine production profiles associated with docetaxel resistance.Analysis of the expression pattern of downstream receptor IL-11RA and enrichment of signal pathway to clarify the potential autocrine mechanism of IL-11.Next, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) was performed to detect the nuclear localization and DNA-binding patterns of phosphorylated STAT4 (pSTAT4). Coimmunoprecipitation and reporter assays were utilized to assess interaction between pSTAT4 and the cotranscription factor CREB-binding protein (CBP) as well as their role in c-MYC transcriptional activity.
Results:
Autocrine secretion of IL-11 was markedly increased in docetaxel-resistant prostate cancer cells. IL-11 stimulation resulted in robust activation of JAK1/STAT4 signalling. Upon activation, pSTAT4 translocated to the nucleus and associated with CBP at the c-MYC promoter region, amplifying its transcriptional activity. Inhibition of the IL-11/IL-11RA interaction or disruption of the JAK1/STAT4 pathway significantly reduced pSTAT4 nuclear entry and its binding to CBP, leading to downregulation of c-MYC expression and restoration of docetaxel sensitivity.
Conclusion:
Our findings identify an autocrine loop of IL-11/IL-11RA that confers docetaxel resistance through the JAK1/STAT4 pathway. The pSTAT4-CBP interaction serves as a critical enhancer of c-MYC transcriptional activity in prostate cancer cells. Targeting this signalling axis presents a potential therapeutic strategy to overcome docetaxel resistance in advanced prostate cancer.
Insights
Docetaxel resistance in prostate cancer is driven by an interleukin-11 (IL-11) autocrine loop, activating JAK1/STAT4 signaling and upregulating c-MYC. Inhibiting this pathway restores docetaxel sensitivity.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling
Background:
- Docetaxel resistance is a major challenge in prostate cancer treatment.
- Understanding cytokine signaling and transcriptional control is crucial for overcoming resistance.
- Novel resistance mechanisms involving autocrine IL-11 signaling were investigated.
Purpose of the Study:
- To elucidate the molecular mechanisms of docetaxel resistance in prostate cancer.
- To identify the role of interleukin-11 (IL-11) and its receptor (IL-11RA) in conferring resistance.
- To investigate the JAK1/STAT4 signaling axis and its impact on c-MYC expression.
Main Methods:
- Single-cell secretion profiling of prostate cancer organoids.
- Analysis of IL-11RA expression and signaling pathway enrichment.
- Chromatin immunoprecipitation sequencing (ChIP-seq) for pSTAT4 binding.
- Coimmunoprecipitation and reporter assays for pSTAT4-CBP interaction and c-MYC activity.
Main Results:
- Docetaxel-resistant cells showed increased autocrine IL-11 secretion.
- IL-11 activated JAK1/STAT4 signaling, leading to pSTAT4 nuclear translocation.
- pSTAT4 associated with CBP at the c-MYC promoter, enhancing transcription.
- Inhibition of IL-11/IL-11RA or JAK1/STAT4 restored docetaxel sensitivity by downregulating c-MYC.
Conclusions:
- An IL-11/IL-11RA autocrine loop confers docetaxel resistance via JAK1/STAT4 signaling.
- The pSTAT4-CBP interaction is critical for c-MYC transcriptional activity.
- Targeting this axis offers a potential therapeutic strategy for advanced prostate cancer.
