Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Department of Urology, Fujian Medical University Union Hospital, Fuzhou, China.
J Exp Clin Cancer Res. 2024 Mar 1;43(1):67. doi: 10.1186/s13046-024-02962-8.
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.
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.
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.
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.
多西紫杉醇耐药是前列腺癌治疗的一个重大障碍。细胞因子信号通路和转录控制机制在癌细胞中的复杂相互作用导致了化疗耐药，但潜在的分子决定因素仍知之甚少。本研究阐明了一种新的耐药机制，即白细胞介素 11（IL-11）与其受体白细胞介素 11 受体亚单位α（IL-11RA）的自分泌相互作用介导，最终激活 JAK1/STAT4 信号轴，并随后转录上调癌基因 c-MYC。
对前列腺癌类器官的单细胞分泌谱进行分析，以确定与多西紫杉醇耐药相关的细胞因子产生谱。分析下游受体 IL-11RA 的表达模式和信号通路富集，以阐明 IL-11 的潜在自分泌机制。接下来，进行染色质免疫沉淀结合高通量测序（ChIP-seq）以检测磷酸化 STAT4（pSTAT4）的核定位和 DNA 结合模式。共免疫沉淀和报告基因检测用于评估 pSTAT4 与共转录因子 CREB 结合蛋白（CBP）之间的相互作用及其在 c-MYC 转录活性中的作用。
多西紫杉醇耐药的前列腺癌细胞中 IL-11 的自分泌明显增加。IL-11 刺激导致 JAK1/STAT4 信号的强烈激活。激活后，pSTAT4 易位到细胞核，并与 c-MYC 启动子区域的 CBP 结合，放大其转录活性。抑制 IL-11/IL-11RA 相互作用或破坏 JAK1/STAT4 途径可显著减少 pSTAT4 的核进入及其与 CBP 的结合，从而下调 c-MYC 的表达并恢复多西紫杉醇的敏感性。
我们的研究结果确定了一种白细胞介素 11/白细胞介素 11 受体的自分泌环，通过 JAK1/STAT4 途径赋予多西紫杉醇耐药性。pSTAT4-CBP 相互作用是前列腺癌细胞中 c-MYC 转录活性的关键增强子。靶向该信号轴为克服晚期前列腺癌中的多西紫杉醇耐药提供了一种潜在的治疗策略。
