Servicio de Oncología Médica, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana (IDIPHISA), Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.
Servicio de Oncología Médica, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana (IDIPHISA), Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.
Free Radic Biol Med. 2019 May 1;135:167-181. doi: 10.1016/j.freeradbiomed.2019.03.009. Epub 2019 Mar 14.
BACKGROUND: Platinum-based chemotherapy remains the standard of care for most lung cancer cases. However chemoresistance is often developed during the treatment, limiting clinical utility of this drug. Recently, the ability of tumor cells to adapt their metabolism has been associated to resistance to therapies. In this study, we first described the metabolic reprogramming of Non-Small Cell Lung Cancer (NSCLC) in response to cisplatin treatment. METHODS: Cisplatin-resistant versions of the A549, H1299, and H460 cell lines were generated by continuous drug exposure. The long-term metabolic changes, as well as, the early response to cisplatin treatment were analyzed in both, parental and cisplatin-resistant cell lines. In addition, four Patient-derived xenograft models treated with cisplatin along with paired pre- and post-treatment biopsies from patients were studied. Furthermore, metabolic targeting of these changes in cell lines was performed downregulating PGC-1α expression through siRNA or using OXPHOS inhibitors (metformin and rotenone). RESULTS: Two out of three cisplatin-resistant cell lines showed a stable increase in mitochondrial function, PGC1-α and mitochondrial mass with reduced glycolisis, that did not affect the cell cycle. This phenomenon was confirmed in vivo. Post-treatment NSCLC tumors showed an increase in mitochondrial mass, PGC-1α, and a decrease in the GAPDH/MT-CO1 ratio. In addition, we demonstrated how a ROS-mediated metabolism reprogramming, involving PGC-1α and increased mitochondrial mass, is induced during short-time cisplatin exposure. Moreover, we tested how cells with increased PGC-1a induced by ZLN005 treatment, showed reduced cisplatin-driven apoptosis. Remarkably, the long-term metabolic changes, as well as the metabolic reprogramming during short-time cisplatin exposure can be exploited as an Achilles' heel of NSCLC cells, as demonstrated by the increased sensitivity to PGC-1α interference or OXPHOS inhibition using metformin or rotenone. CONCLUSION: These results describe a new cisplatin resistance mechanism in NSCLC based on a metabolic reprogramming that is therapeutically exploitable through PGC-1α downregulation or OXPHOS inhibitors.
背景：铂类化疗仍然是大多数肺癌病例的标准治疗方法。然而，在治疗过程中经常会产生化疗耐药性，从而限制了这种药物的临床应用。最近，肿瘤细胞适应代谢的能力与对治疗的耐药性有关。在这项研究中，我们首先描述了非小细胞肺癌（NSCLC）对顺铂治疗的代谢重编程。
方法：通过连续药物暴露生成了 A549、H1299 和 H460 细胞系的顺铂耐药版本。分析了亲本和顺铂耐药细胞系中顺铂治疗的长期代谢变化以及早期反应。此外，还研究了对 4 个患者来源的异种移植模型进行顺铂治疗以及从患者中获得的配对治疗前和治疗后活检。此外，通过 siRNA 下调 PGC-1α 表达或使用 OXPHOS 抑制剂（二甲双胍和鱼藤酮）对这些细胞系中的变化进行代谢靶向。
结果：三株顺铂耐药细胞系中有两株表现出稳定的线粒体功能增加、PGC1-α 和线粒体质量增加，同时糖酵解减少，但不影响细胞周期。这一现象在体内得到了证实。治疗后 NSCLC 肿瘤显示线粒体质量、PGC-1α 增加，以及 GAPDH/MT-CO1 比值降低。此外，我们证明了 ROS 介导的代谢重编程如何在短时间顺铂暴露期间涉及 PGC-1α 和增加的线粒体质量。此外，我们测试了 ZLN005 治疗诱导的 PGC-1a 增加如何导致细胞对顺铂驱动的凋亡减少。值得注意的是，正如通过 PGC-1α 干扰或使用二甲双胍或鱼藤酮抑制 OXPHOS 所证明的那样，长期代谢变化以及短时间顺铂暴露期间的代谢重编程可作为 NSCLC 细胞的阿喀琉斯之踵。
结论：这些结果描述了一种基于代谢重编程的新的 NSCLC 顺铂耐药机制，通过下调 PGC-1α 或使用 OXPHOS 抑制剂可进行治疗性利用。
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