39 - Freie Mitteilung
Clinical works I
16. Mai 2019, 08:30 - 10:00, Bellavista 2, 6. OG
Increased mitochondrial mass is associated with cisplatin resistance and pemetrexed sensitivity in non-small cell lung cancer cells
T. M. Marti, Y. Gao, P. Dorn, S. Liu, H. Deng, R. W. Peng, S. R. Hall, G. Kocher, R. A. Schmid, Presenter: Y. Gao (Bern)
Lung cancer in both men and women is the leading cause of cancer-related deaths. More than 80% of lung tumors are non-small-cell lung cancers (NSCLC). Cisplatin plus pemetrexed combination therapy is considered the standard treatment for patients with advanced non-squamous NSCLC. However, advanced NSCLC has a low 5-year survival rate of approximately 30%. This is mainly due to the development of therapy resistance. We previously showed that the NSCLC cell line A549 harbors different subpopulations including a mesenchymal-like subpopulation featuring increased chemo- and radiotherapy resistance. Very recently, therapy resistance in hematological and solid tumors has been associated with increased mitochondrial activity. Thus, the aim of this study was to investigate the role of the mitochondrial activity in NSCLC chemotherapy resistance.
Mito Tracker was used to stain the mitochondrial mass of the mesenchymal-like population from NSCLC cell line A549. Real Time PCR(RT-PCR) was used to quantify the mitochondrial DNA copy number. FACS (Fluorescence-Activated Cell Sorting) was used to sort two subpopulations Mito-High (10%) and Mito-Low (10%). The cisplatin and pemetrexed response of these two populations was tested by colony formation assay.
After pemetrexed treatment, mitochondrial mass increased in parental A549 cells over time. A549 mito-HIGH subpopulation cells featured a significant increase in mitochondrial DNA copy numbers relative to Mito-LOW cells indicating phenotypically distinct subpopulations can be isolated by our FACS sorting strategy. The proliferation rate of Mito-HIGH cells was significantly increased. Mito-HIGH subpopulation cells was more resistant to cisplatin treatment compared to mito-LOW cells. Interestingly, Mito-HIGH cells were sensitive to pemetrexed treatment compared to Mito-LOW cells.
This study revealed that the level of mitochondrial mass is positively associated with cisplatin resistance in the mesenchymal-like A549 subpopulation. In contrast, high levels of mitochondrial mass confer pemetrexed sensitivity. Thus, cisplatin resistant cells characterized by high levels of mitochondrial mass are susceptible to pemetrexed treatment, which could explain the increased efficiency of the combination therapy in the clinical setting.