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. 2018 Sep 13;8:13762. doi: 10.1038/s41598-018-32195-7

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Molecular mechanisms underlying the chemoresistance of HTLA-ER cells. This figure illustrates the observed molecular mechanisms underlying chemoresistance of HTLA-ER cells and the events leading to apoptosis in etoposide sensitive HTLA parental cells. Left panel: Short-term treatment with etoposide of HTLA-230 cells reduces oxidative phosphorylation and decreases glutathione (GSH) levels inducing reactive oxygen species (ROS) overproduction, thus leading to DNA damage (H2AX). Consequently, etoposide-induced genotoxic stress increases pro-apoptotic Bax, reduces anti-apoptotic Bcl2 and stimulates P53-Ser15 phosphorylation, two events leading to apoptosis and chemosensitivity. Right panel: HTLA-ER cells are able to efficiently counteract etoposide-induced ROS production by maintaining an efficient aerobic metabolism and increasing GSH levels. Long-term treatment with etoposide causes a deletion of the 13q14.3 locus and the consequent downregulation of miRNAs 15a/16-1, stimulating several pro-survival signals which contribute to inducing chemoresistance.