文章：

检查点激酶1抑制剂联合低剂量羟基脲促进黑色素瘤中ATM激活的NF-κB依赖性促炎趋化因子表达

Checkpoint Kinase 1 Inhibitor Combined with Low Dose Hydroxyurea Promotes ATM-Activated NF-κB-Dependent Pro-Inflammatory Chemokine Expression in Melanomas

原文发布日期：29 May 2025

DOI: 10.3390/cancers17111817

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: Melanoma has a rising incidence worldwide. Current treatments are effective, although the development of resistance is common. A novel anti-cancer treatment using checkpoint kinase 1 inhibitor (CHK1i), SRA737, in combination with low-dose hydroxyurea (LDHU), has been demonstrated to effectively kill tumour cells and promote an anti-tumour immune response through the treatment-induced release of pro-inflammatory chemokines and cytokines. These chemokines/cytokines modify the tumour microenvironment from an immunosuppressive to an inflamed state to recruit anti-tumour immune cells. Methods: A panel of human melanoma cell lines was assessed using a panel of chemokines and cytokine expression, and the mechanism of their regulation was investigated. Results: We demonstrate that SRA737 + LDHU upregulates pro-inflammatory chemokines in human melanoma cells in response to SRA737 + LDHU through the ATM-NF-κB signalling pathway. The increased chemokine expression corresponded to the increase in secretion of pro-inflammatory chemokines from tumour cells following SRA737 + LDHU treatment. However, inhibiting NF-κB and ATM did not affect SRA737 + LDHU-induced cell killing. Increased expression of non-NF-κB target genes with SRA737 + LDHU suggests that other transcriptional pathways are also activated and may contribute to the increasing cytokine/chemokine gene expression in response to treatment. Conclusions: SRA737 + LDHU upregulates pro-inflammatory chemokine expression through an ATM-NF-κB-dependent mechanism.

摘要翻译： 

背景/目的：黑色素瘤在全球范围内的发病率呈上升趋势。现有治疗方法虽有效，但耐药性发展较为常见。一种新型抗癌疗法采用检查点激酶1抑制剂（CHK1i）SRA737联合低剂量羟基脲（LDHU），已被证实能有效杀伤肿瘤细胞，并通过治疗诱导释放的促炎性趋化因子和细胞因子来促进抗肿瘤免疫反应。这些趋化因子/细胞因子将肿瘤微环境从免疫抑制状态转变为炎症状态，从而招募抗肿瘤免疫细胞。方法：通过检测一组趋化因子和细胞因子的表达，评估了一系列人类黑色素瘤细胞系，并研究了其调控机制。结果：我们证明SRA737 + LDHU通过ATM-NF-κB信号通路上调人类黑色素瘤细胞中促炎性趋化因子的表达。趋化因子表达的增加与SRA737 + LDHU治疗后肿瘤细胞分泌促炎性趋化因子的增加相对应。然而，抑制NF-κB和ATM并不影响SRA737 + LDHU诱导的细胞杀伤作用。SRA737 + LDHU处理下非NF-κB靶基因表达的增加表明，其他转录通路也被激活，并可能促进细胞因子/趋化因子基因表达对治疗的反应性增强。结论：SRA737 + LDHU通过ATM-NF-κB依赖机制上调促炎性趋化因子的表达。

原文链接：

Checkpoint Kinase 1 Inhibitor Combined with Low Dose Hydroxyurea Promotes ATM-Activated NF-κB-Dependent Pro-Inflammatory Chemokine Expression in Melanomas