Repression of the BH3-only molecule PMAIP1/Noxa impairs glucocorticoid sensitivity of acute lymphoblastic leukemia cells |
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Authors: | Christian Ploner Johannes Rainer Susanne Lobenwein Stephan Geley Reinhard Kofler |
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Institution: | 1. Division Molecular Pathophysiology, Biocenter, Medical University of Innsbruck, Fritz-Pregl-Stra?e 3, 6020, Innsbruck, Austria 2. Tyrolean Cancer Research Institute, 6020, Innsbruck, Austria
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Abstract: | Glucocorticoid (GC)-induced apoptosis plays a major role in the treatment of acute lymphoblastic leukemia (ALL) and related
malignancies. Members of the BCL2 family of pro- and anti-apoptotic proteins are regulated by GC, but to what extent these
regulations contribute to GC-induced cell death and resistance development is poorly understood. Using primary lymphoblasts
from ALL children during systemic GC monotherapy and related cell lines, we have previously shown that the response of the
BCL2 rheostat to GC was dominated by induction of the pro-apoptotic BH3-only molecules BMF and BCL2L11/Bim, but we also observed
an unexpected significant repression of the pro-apoptotic BCL2 protein PMAIP1/Noxa. Here, we report that GC represses Noxa
mRNA levels and also interferes with its protein stability in a proteasome-dependent manner. Prevention of GC-mediated Noxa
repression by conditional expression of transgenic Noxa changed the kinetics of GC-induced apoptosis to resemble cell death
induced by BimEL alone. Hence, GC appear to activate functionally relevant pro- as well as anti-apoptotic pathways in ALL
cells. Interfering with the anti-apoptotic component of the GC response might contribute to improved therapeutic approaches
and circumvention of resistance to this therapy. |
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Keywords: | Acute lymphoblastic leukemia PMAIP1/Noxa Glucocorticoid-induced apoptosis BCL2 family Functional gene analysis |
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