Bueno 2016 Thesis
|Bueno e Silva MM (2016) Alterações mitocondriais e reprogramação metabólica em células de glioblastoma após tratamento com temozolomida. Dissertation p71.|
Abstract: Mitochondria play vital cellular functions. These organelles functions and roles in cellular metabolism not surprisingly have been implicated in a broad spectrum of diseases, including neurodegeneration and cancer. Lately, it has been given an important role for mitochondria and cellular metabolism in response and resistance of tumour cells to therapy. Given the central role of mitochondria in cellular homeostasis, we evaluated mitochondria network alterations in glioblastoma cells in response to treatment with the chemotherapeutic Temozolomide (TMZ). The acute treatment with TMZ induced an increase in both mitochondrial mass and mitochondrial membrane potential (MMP) 5 days after treatment, followed by a decrease in the same parameters on day 7. The increase in these parameters is accompanied by a decrease in PGC1a expression on day 3 and a progressive increase in autophagy levels, suggesting that the increase in mitochondrial mass is independent of PGC1a and may be due to an accumulation of mitochondria. Also, the increase in mitochondrial mass and MMP correlates with higher levels of oxidative stress and senescence on day 5. We also evaluated mitochondrial oxygen consumption in both control and treated with TMZ cells, observing that 5 days after treatment with TMZ cells have higher oxygen consumption rates and a higher reserve capacity. In order to understand how mitochondrial alterations influence the response to chemotherapy, we treated the cells previously treated with TMZ on D5 with glycolysis and OXPHOS inhibitors and followed cell number. Results suggest that these inhibitors abrogate TMZ treated cells proliferation. Also, TMZ-treated cells are more sensitive to OXPHOS inhibition than control cells, suggesting that TMZ reprograms the cells metabolism to a more oxidative state instead of a glycolytic one.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Cancer
Organism: Human Tissue;cell: Nervous system, Other cell lines Preparation: Intact cells
Regulation: Inhibitor Coupling state: LEAK, ROUTINE, ET