Thyroid hormone enhances efficacy of cisplatin in lung cancer patients via down-regulating GLUT1 expression and reversing the Warburg effect

• Published in: Mitochondrion 2024-09, Vol.78, p.101919, Article 101919
• Main Authors: Fan, Chenchen, Ren, Yanbei, Zhang, Wen, Wen, Jing, Zhang, Wenjia, Lin, Shumeng, Bai, Yidong, Zheng, Tiansheng, Abay, Baigenzhin, Li, Ming, Fan, Lihong
• Format: Article
• Language: English
• Subjects: A549 Cells; Aged; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; Down-Regulation; Female; Gene Expression Regulation, Neoplastic - drug effects; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 1 - metabolism; Glycolysis - drug effects; Humans; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Male; Middle Aged; Mitochondria; Thyroid hormones; Thyroid Hormones - metabolism; Tumor metabolism; Warburg effect; Warburg Effect, Oncologic - drug effects
• ISSN: 1567-7249; 1872-8278; 1872-8278
• DOI: 10.1016/j.mito.2024.101919

•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 found that advanced NSCLC patients with relatively-high free T3 have a longer progression-free survival when treated with cisplatin chemotherapy.•Cytological experiments in vitro show that thyroid hormone can increase the sensitivity of lung cancer cells to cisplatin, and the specific mechanism is as follows: Combined use of thyroid hormone and cisplatin down-regulated the expression of MSI1 in lung cancer cells A549 and PC9, decreased the phosphorylation level of AKT and the expression of GLUT1, thereby reducing glycolysis and reversing Warburg effect. Moreover, increasing ROS content in lung cancer cells and reducing MMP, ultimately enhanced the impact of cisplatin on lung cancer cell death. 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 thyroi