文章：

慢性IL-1暴露减弱前列腺癌细胞系中RELA和STAT3依赖的协同细胞因子信号传导

Chronic IL-1 Exposure Attenuates RELA- and STAT3-Dependent Synergistic Cytokine Signaling in Prostate Cancer Cell Lines

原文发布日期：26 November 2025

DOI: 10.3390/cancers17233778

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: The milieu of inflammatory cytokines present in the prostate cancer (PCa) tumor microenvironment exerts various effects on cancer progression. Chronic exposure to the inflammatory cytokine interleukin-1 (IL-1) has been shown to impact signaling via the RELA/NF-kB pathway; however, the effects of chronic inflammation on the integration of different inflammatory signaling pathways, such as the interleukin-6 (IL-6)/STAT3 axis, requires further exploration. Methods: We generated in vitro subline models by exposing the C4-2 and LNCaP PCa cell lines to either IL-1α or IL-1β for several months. We then treated the resulting sublines with acute IL-1 alone, IL-6 alone, or IL-1/IL-6 in combination and assessed for sensitivity to cytokine signaling. We observed changes in proliferation and quantified using Ki-67 immunostaining. Cell proliferation was assessed after siRNA silencingRELAorSTAT3. Results: IL-1/IL-6 signaling in combination enhanced the signaling effects of either cytokine alone, particularly cytostasis. While the chronic IL-1 sublines maintained sensitivity to acute IL-6 signaling, they lost sensitivity to acute IL-1 signaling and did not show the enhanced IL-1/IL-6 cytostatic response. Inhibition ofRELAandSTAT3rescued cytostasis after IL-1/IL-6 treatment in parental PCa cell lines, but onlySTAT3inhibition rescued proliferation in the chronic IL-1 sublines. Conclusions: Our work shows that IL-1/RELA and IL-6/STAT3 work in parallel to synergistically induce cytostasis. However, chronic IL-1 exposure selects for cells that attenuate IL-1/RELA signaling, subsequently attenuating IL-1/IL-6 synergy.

摘要翻译： 

背景/目的：前列腺癌（PCa）肿瘤微环境中存在的炎性细胞因子对癌症进展产生多种影响。长期暴露于炎性细胞因子白细胞介素-1（IL-1）已被证明会影响通过RELA/NF-κB通路的信号传导；然而，慢性炎症对不同炎性信号通路（如白细胞介素-6（IL-6）/STAT3轴）整合的影响仍需进一步探索。方法：我们通过将C4-2和LNCaP前列腺癌细胞系暴露于IL-1α或IL-1β数月，建立了体外亚系模型。随后，我们对所得亚系分别进行急性IL-1单独处理、IL-6单独处理或IL-1/IL-6联合处理，并评估其对细胞因子信号传导的敏感性。我们观察了增殖变化，并使用Ki-67免疫染色进行量化。在通过siRNA沉默RELA或STAT3后评估细胞增殖情况。结果：IL-1/IL-6联合信号传导增强了任一细胞因子单独的信号效应，尤其是细胞生长抑制。虽然慢性IL-1亚系对急性IL-6信号传导保持敏感性，但它们对急性IL-1信号传导失去敏感性，且未表现出增强的IL-1/IL-6细胞生长抑制反应。在亲本前列腺癌细胞系中，抑制RELA和STAT3可挽救IL-1/IL-6处理后的细胞生长抑制，但在慢性IL-1亚系中，仅STAT3抑制能挽救细胞增殖。结论：我们的研究表明，IL-1/RELA和IL-6/STAT3并行作用，协同诱导细胞生长抑制。然而，长期暴露于IL-1会选择那些减弱IL-1/RELA信号传导的细胞，从而减弱IL-1/IL-6的协同作用。

原文链接：

Chronic IL-1 Exposure Attenuates RELA- and STAT3-Dependent Synergistic Cytokine Signaling in Prostate Cancer Cell Lines