Details

Autor(en) / Beteiligte

• Cruz-Bermúdez, Alberto
• Laza-Briviesca, Raquel
• Vicente-Blanco, Ramiro J.
• García-Grande, Aránzazu
• Coronado, Maria José
• Laine-Menéndez, Sara
• Palacios-Zambrano, Sara
• Moreno-Villa, M. Rocío
• Ruiz-Valdepeñas, Asunción Martin
• Lendinez, Cristina
• Romero, Atocha
• Franco, Fernando
• Calvo, Virginia
• Alfaro, Cristina
• Acosta, Paloma Martin
• Salas, Clara
• Garcia, José Miguel
• Provencio, Mariano

Titel

Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition

Ist Teil von

• Free radical biology & medicine, 2019-05, Vol.135, p.167-181

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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). 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. 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. [Display omitted] •NSCLC cisplatin-resistant cells show increased PGC-1α expression and oxidative metabolism.•Cisplatin treatment induces an increase in mitochondrial function mediated by ROS.•This metabolism can be therapeutically exploited through PGC-1α or OXPHOS regulation.