Repression of the BH3-only molecule PMAIP1/Noxa impairs glucocorticoid sensitivity of acute lymphoblastic leukemia cells
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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.
KeywordsAcute lymphoblastic leukemia PMAIP1/Noxa Glucocorticoid-induced apoptosis BCL2 family Functional gene analysis
We thank Dr. M. J. Ausserlechner for providing the pQ-tetCMV-Noxa-SV40-Neo plasmid, Dr. A. Villunger for helpful discussions, B. Gschirr, A. Kofler, and C. Mantinger for technical assistance, and M. Kat Occhipinti-Bender for editing the manuscript. Supported by grants from the Austrian Science Fund (SFB-F021, P18747) and by ONCOTYROL, a COMET Center funded by the Austrian Research Promotion Agency (FFG), the Tiroler Zukunftsstiftung and the Styrian Business Promotion Agency (SFG). The Tyrolean Cancer Research Institute is supported by the “Tiroler Landeskrankenanstalten Ges.m.b.H. (TILAK)”, the “Tyrolean Cancer Aid Society”, various businesses, financial institutions and the People of Tyrol.
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