Muralidharan Janani, Eswaran Murugesh, Bae Sejong, Singh Shailesh, Mir Hina
Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA, USA.
Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA, USA; Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA, USA.
Biomed Pharmacother. 2025 Aug;189:118258. doi: 10.1016/j.biopha.2025.118258. Epub 2025 Jun 21.
Conventional chemotherapeutics for colon cancer often fail to achieve optimal clinical outcomes, as many patients develop resistance and experience significant toxicity, thereby increasing the overall health burden. Understanding the mechanisms conferring resilience to cancer cells is essential for developing more effective therapies. 5-Flourouracil (5FU) is the standard of care used for colon cancer. 5FU-associated inflammation, characterized by a change in cytokine profile, enables the colon cancer cells to evade cell death, thereby undermining the cytotoxic effects of the drug. Current study underscores the significance of CCL20 signaling, which is linked to inflammatory conditions and is elevated during colon carcinogenesis, in tempering the cytotoxic effects of 5FU. The presented data demonstrate an inverse correlation between CCL20 concentrations in colon cancer and sensitivity to 5FU. Moreover, treatment with 5FU further stimulates CCL20 signaling in colon cancer cells, likely via increased fatty acid efflux. Notably, the findings reveal that IL10 signaling is under negative regulation of CCL20. Additionally, exposure to 5FU elevates IL10 levels, thus creating a complex interplay of pro-inflammatory and anti-inflammatory pathways. Such dual activation of contrasting mechanisms undermines the therapeutic efficacy of 5FU. Therefore, the insights gained from this study emphasize the significance of addressing immune signatures characterized by CCL20 and IL10 to enhance the effectiveness of 5FU in colon cancer treatment.
结肠癌的传统化疗方法往往无法实现最佳临床疗效，因为许多患者会产生耐药性并经历严重毒性反应，从而增加了整体健康负担。了解赋予癌细胞抗逆性的机制对于开发更有效的治疗方法至关重要。5-氟尿嘧啶（5FU）是用于结肠癌的标准治疗药物。5FU相关的炎症以细胞因子谱的变化为特征，使结肠癌细胞能够逃避细胞死亡，从而削弱了该药物的细胞毒性作用。当前研究强调了CCL20信号传导的重要性，其与炎症状态相关且在结肠癌发生过程中升高，可调节5FU的细胞毒性作用。所呈现的数据表明结肠癌中CCL20浓度与对5FU的敏感性呈负相关。此外，用5FU治疗进一步刺激结肠癌细胞中的CCL20信号传导，可能是通过增加脂肪酸外流实现的。值得注意的是，研究结果表明IL10信号传导受CCL20的负调控。此外，暴露于5FU会升高IL10水平，从而形成促炎和抗炎途径的复杂相互作用。这种相反机制的双重激活削弱了5FU的治疗效果。因此，本研究获得的见解强调了应对以CCL20和IL10为特征的免疫特征对于提高5FU在结肠癌治疗中的有效性的重要性。
