Abstract 4803: Mitochondrial response to temozolomide treatment in glioma cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-08, Vol.80 (16_Supplement), p.4803-4803
• Main Authors: Lenz, Luana S., Silva, Mardja M., Bristot, Ivi J., Klamt, Fabio, Lenz, Guido
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2020-4803

Mitochondria are a central organelle to metabolism and apoptosis control, it means that their functionality is essential to cellular homeostasis. We investigated the mitochondrial alterations in respose to the chemotherapeutic Temozolomide (TMZ) in glioma cells.We transduced A172 and U87 cells with a fluorescent protein targeted to mitochondria (Addgene #50057), treated these cell with TMZ 100 uM during 3 hours and analyzed them by cytometry, microscopy and high resolution respirometry at days 3, 5 and 7 after treatment.Once tolerance is a dynamic process that can lead to different responses even between related cells, we first asked how related cells respond to TMZ in terms of mitochondria amount. Closely related sisters and cousins cells were not different to random pairs, indicating that mitochondria amount is not inherited and that this feature is very dynamics. Population analysis reveal that five days after TMZ the cells showed an increase in mitochondrial mass and mitochondrial swelling. The PGC-1 expression was reduced by half on day 3, suggesting that increase in mitochondrial mass must be due to accumulation of mitochondria instead of biogenesis. Five days after treatment we observed an increase in mitochondrial membrane potential measure by JC1 and an increase in mitochondria ATP linked respiration. To test if increased mitochondria respiration is a therapeutically targetable adaptation of these cells treated with TMZ, we treated the cells that survived five days after TMZ with KCN, a cytochrome c oxidase inhibitor. As expected, the TMZ-treated cells were more sensitive to the blockage of mitochondrial respiration than untreated cells. On the other hand, cells treated at day five after TMZ with 2-DG, a glycolysis inhibitor, were less affected, indicating that the oxidative phosphorylation is important to tolerance to TMZ.Our results indicate that treatment induce a metabolic reprogramming with increase in oxidative state, and strategies to overcome this tolerance mechanism could be explored. Citation Format: Luana S. Lenz, Mardja M. Silva, Ivi J. Bristot, Fabio Klamt, Guido Lenz. Mitochondrial response to temozolomide treatment in glioma cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4803.