Fan Chenchen, Ren Yanbei, Zhang Wen, Wen Jing, Zhang Wenjia, Lin Shumeng, Bai Yidong, Zheng Tiansheng, Abay Baigenzhin, Li Ming, Fan Lihong
Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Institute of Energy Metabolism and Health, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Mitochondrion. 2024 Sep;78:101919. doi: 10.1016/j.mito.2024.101919. Epub 2024 Jun 12.
Cisplatin (CDDP) is a standard non-small cell lung cancer (NSCLC) chemotherapy, but its efficacy is hampered by resistance, partly due to the Warburg effect. This study investigates how thyroid hormones enhance the Warburg effect, increasing sensitivity to cisplatin in lung cancer. Clinical data from advanced NSCLC patients were analyzed based on thyroid hormone levels, categorizing patients into high and low groups. Cellular experiments involved Control, 10uM CDDP, 10uM CDDP + 0.1uM T3, and 10uM CDDP + 0.1uM T4 categories. Parameters were measured in A549 and PC9 lung cancer cells, including proliferation, apoptosis, mitochondrial membrane potential, ROS production, glycolysis enzyme activity, lactic acid level, and ATP content. Gene and protein expressions were assessed using qPCR and Western Blot. Analysis revealed higher FT3 levels correlated with prolonged progression-free survival before chemotherapy (median PFS: high FT3 group = 12.67 months, low FT3 group = 7.03 months, p = 0.01). Cellular experiments demonstrated that thyroid hormones increase lung cancer cell sensitivity to cisplatin, inhibiting proliferation and enhancing efficacy. The mechanism involves thyroid hormones and cisplatin jointly down-regulating MSI1/AKT/GLUT1 expression, reducing lactic acid and glycolysis. This Warburg effect reversal boosts ATP levels, elevates ROS, and decreases MMP, enhancing cisplatin effectiveness in A549 and PC9 cells. In conclusion, elevated free T3 levels in advanced NSCLC patients correlate with prolonged progression-free survival under cisplatin chemotherapy. Cellular experiments reveal that thyroid hormones enhance lung cancer cell sensitivity to cisplatin by reversing the Warburg effect, providing a mechanistic basis for improved therapeutic outcomes.
顺铂（CDDP）是一种标准的非小细胞肺癌（NSCLC）化疗药物，但其疗效因耐药性而受到阻碍，部分原因是瓦伯格效应。本研究调查甲状腺激素如何增强瓦伯格效应，增加肺癌对顺铂的敏感性。基于甲状腺激素水平分析了晚期NSCLC患者的临床数据，将患者分为高、低两组。细胞实验包括对照组、10μM顺铂组、10μM顺铂 + 0.1μM T3组和10μM顺铂 + 0.1μM T4组。在A549和PC9肺癌细胞中测量了包括增殖、凋亡、线粒体膜电位、ROS产生、糖酵解酶活性、乳酸水平和ATP含量等参数。使用qPCR和蛋白质印迹法评估基因和蛋白质表达。分析显示，较高的FT3水平与化疗前无进展生存期延长相关（中位无进展生存期：高FT3组 = 12.67个月，低FT3组 = 7.03个月，p = 0.01）。细胞实验表明，甲状腺激素增加肺癌细胞对顺铂的敏感性，抑制增殖并增强疗效。其机制涉及甲状腺激素和顺铂共同下调MSI1/AKT/GLUT1表达，减少乳酸和糖酵解。这种瓦伯格效应的逆转提高了ATP水平，升高了ROS，并降低了MMP，增强了顺铂在A549和PC9细胞中的有效性。总之，晚期NSCLC患者游离T3水平升高与顺铂化疗下无进展生存期延长相关。细胞实验表明，甲状腺激素通过逆转瓦伯格效应增强肺癌细胞对顺铂的敏感性，为改善治疗结果提供了机制基础。
