Mitochondrial changes are important for the tamoxifen-resistant cells to survive the therapy
Veronika Tomkova1, Cristian Sandoval-Acuña1, Sandra Lettlova1, Jaroslav Truksa1 1Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic
Tamoxifen resistance represents a big clinical issue in the treatment of breast cancer patients. Despite of the continuous development of new therapeutical approaches, approximately 30-50% of patients become resistant to tamoxifen. It has been shown that tamoxifen not only affects estrogen signaling but is also able to change mitochondrial function. Its accumulation within mitochondria changes cell respiration, fatty acid oxidation and mitochondrial DNA synthesis. Moreover, some of the mitochondrial complexes of electron transport chain are targets for tamoxifen. For this reason, we hypothesized that mitochondria play an important role in tamoxifen resistance. In order to answer this question, we generated TamR cell lines MCF7 Tam5R and T47D Tam5R derived from the parental cell lines. Our results clearly show the differences between parental and TamR cell lines in terms of lower respiration and higher dependence on glycolysis in TamR cell lines as shown by increased lactate production and higher sensitivity to 2-deoxyglucose. TamR cells have also reduced formation and activity of mitochondrial supercomplexes, resulting in higher mitochondrial reactive oxygen species production. Moreover, results from confocal microscopy and flow cytometry indicate differences in the dynamics and amount of mitochondria between parental and TamR cells. Importantly, a comparable phenotype can be seen in the model of cell line with dysfunctional mitochondria (rho zero cells) which do not respond to tamoxifen treatment, similarly to TamR cells. Based on our results we suggest that mitochondria in TamR cells undergo changes that help them survive tamoxifen treatment.
Grant support: This work has been supported by GACR grant 16-12816S and Kellner Family Foundation to J.T. and also by the MEYS of CR within the LQ1604 National Sustainability Program II (Project BIOCEV-FAR)
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