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Mechanisms of resistance to apoptosis in the human acute promyelocytic leukemia cell line NB4

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Abstract

Current frontline therapies have improved overall survival in acute promyelocytic leukemia (APL) patients to exceptional rates; however, relapse is still a problem among high-risk and old patients. Therefore, the development of better and safer therapies continues to be a goal in the treatment of this disease. In the present work, we examined three different pathways that hinder cell death in the APL cell line NB4, shedding light on the mechanisms that underlie resistance to apoptosis in these cells and that might help provide them with a proliferative advantage. We found that the proteasome inhibitor MG-132 specifically induces in NB4 cells an Nrf2-mediated antioxidant response which counteracts mitochondria-dependent apoptosis induced by the lipophilic cation dequalinium. More importantly, we also demonstrated that high basal autophagy levels and the gain-of-function of mutant p53 are intrinsic mechanisms of resistance to apoptosis in this cell line. According to our results, the pharmacological inhibition of autophagy and p53 mutants are useful tools to explore resistance to apoptosis in APL and other types of cancer and could be the bases of new therapeutic approaches that improve the efficiency and allow dose reduction of the current treatments.

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Acknowledgments

Authors wish to thank Nadia Ashour and Dr. Santiago Ropero, from the University of Alcalá, for their invaluable help during the revision of this manuscript. This work was supported by Instituto de Salud Carlos III (PI06/0119), Comunidad de Madrid-University of Alcalá (CCG10-UAH/SAL-5966), and University of Alcalá (UAH GC2009-001; UAH 2011/BIO-006). Irene Gañán-Gomez was funded by the Human Resources Promotion Program of the Regional Plan for Scientific Research, Technological Development and Innovation 2005–2010 (Plan Regional para la Investigación Científica, Desarrollo Tecnológico e Innovación, PRINCET) from Junta de Comunidades de Castilla-la Mancha (Spain) and the European Social Fund (ESF) 2007/2013.

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Authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of System Biology, Unit of Biochemistry and Molecular Biology, Faculty of Medicine and Health Sciences, University of Alcalá (UAH), Carretera Madrid-Barcelona Km 33.6 s/n, 28871, Alcalá de Henares, Madrid, Spain

    I. Gañán-Gómez, P. Sancho & M. C. Boyano-Adánez

  2. Department of Cellular and Molecular Medicine, Biological Research Centre (CIB), Ramiro de Maeztu 9, 28040, Madrid, Spain

    M. C. Estañ-Omaña & P. Aller

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  1. I. Gañán-Gómez
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Gañán-Gómez, I., Estañ-Omaña, M.C., Sancho, P. et al. Mechanisms of resistance to apoptosis in the human acute promyelocytic leukemia cell line NB4. Ann Hematol 94, 379–392 (2015). https://doi.org/10.1007/s00277-014-2237-3

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