Han Bingjie, Sun Yuanyuan, Zhang Xiaofen, Yue Ping, Tian Meiling, Yan Dan, Yin Fanxiang, Qin Bo, Zhao Yi
Department of Translational Medical Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Front Pharmacol. 2022 Jul 14;13:942261. doi: 10.3389/fphar.2022.942261. eCollection 2022.
The occurrence of cisplatin resistance is still the main factor limiting the therapeutic effect of non-small cell lung cancer (NSCLC). It is urgent to elucidate the resistance mechanism and develop novel treatment strategies. Targeted metabolomics was first performed to detect amino acids' content in cisplatin-resistant cancer cells considering the relationship between tumour metabolic rearrangement and chemotherapy resistance and chemotherapy resistance. We discovered that levels of most amino acids were significantly downregulated, whereas exogenous supplementation of proline could enhance the sensitivity of NSCLC cells to cisplatin, evidenced by inhibited cell viability and tumour growth and xenograft models. In addition, the combined treatment of proline and cisplatin suppressed ATP production through disruption of the TCA cycle and oxidative phosphorylation. Furthermore, transcriptomic analysis identified the cell cycle as the top enriched pathway in co-therapy cells, accompanied by significant down-regulation of PLK1, a serine/threonine-protein kinase. Mechanistic studies revealed that PLK1 inhibitor (BI2536) and CDDP have synergistic inhibitory effects on NSCLC cells, and cells transfected with lentivirus expressing shPLK1 showed significantly increased toxicity to cisplatin. Inhibition of PLK1 inactivated AMPK, a primary regulator of cellular energy homeostasis, ultimately leading to cell cycle arrest via FOXO3A-FOXM1 axis mediated transcriptional inhibition in cisplatin-resistant cells. In conclusion, our study demonstrates that exogenous proline exerts an adjuvant therapeutic effect on cisplatin resistance, and PLK1 may be considered an attractive target for the clinical treatment of cisplatin resistance in NSCLC.
顺铂耐药的发生仍然是限制非小细胞肺癌（NSCLC）治疗效果的主要因素。阐明耐药机制并开发新的治疗策略迫在眉睫。考虑到肿瘤代谢重排与化疗耐药之间的关系，首次进行靶向代谢组学检测顺铂耐药癌细胞中氨基酸的含量。我们发现大多数氨基酸水平显著下调，而外源性补充脯氨酸可增强NSCLC细胞对顺铂的敏感性，这在细胞活力抑制、肿瘤生长抑制以及异种移植模型中得到证实。此外，脯氨酸和顺铂联合治疗通过破坏三羧酸循环和氧化磷酸化抑制ATP生成。此外，转录组分析确定细胞周期是联合治疗细胞中富集程度最高的通路，同时丝氨酸/苏氨酸蛋白激酶PLK1显著下调。机制研究表明，PLK1抑制剂（BI2536）和顺铂对NSCLC细胞具有协同抑制作用，用表达shPLK1的慢病毒转染的细胞对顺铂的毒性显著增加。在顺铂耐药细胞中，抑制PLK1会使细胞能量稳态的主要调节因子AMPK失活，最终通过FOXO3A-FOXM1轴介导的转录抑制导致细胞周期停滞。总之，我们的研究表明外源性脯氨酸对顺铂耐药具有辅助治疗作用，PLK1可能被认为是NSCLC顺铂耐药临床治疗的一个有吸引力的靶点。
