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Title

Mechanism of apoptosis induced by IFN-α in human myeloma cells: Role of Jak1 and Bim and potentiation by rapamycin

AuthorsGómez-Benito, Maria; Carvajal-Vergara, Xonia; Pandiella, Atanasio
Issue Date2007
PublisherElsevier
CitationCellular Signalling 19(4): 844-854 (2007)
AbstractInterferon-α (IFN-α) has been used for the last 20 years in the maintenance therapy of multiple myeloma (MM), though it is only effective in some patients. Congruent with this, IFN-α induces apoptosis in some MM cell lines. Understanding the mechanism of IFN-α-induced apoptosis could be useful in establishing criteria of eligibility for therapy. Here we show that IFN-α-induced apoptosis in the MM cell lines U266 and H929 was completely blocked by a specific inhibitor of Jak1. The mTOR inhibitor rapamycin mitigated apoptosis in U266 but potentiated it in H929 cells. IFN-α induced PS exposure, ΔΨm loss and pro-apoptotic conformational changes of Bak, but not of Bax, and was fully prevented by Mcl-1 overexpression in U266 cells. IFN-α treatment caused the release of cytochrome c from mitochondria to cytosol and consequently, a limited proteolytic processing of caspases. Apoptosis induced by IFN-α was only slightly prevented by caspase inhibitors. Levels of the BH3-only proteins PUMA and Bim increased during IFN-α treatment. Bim increase and apoptosis was prevented by transfection with the siRNA for Bim. PUMA-siRNA transfection reduced electroporation-induced apoptosis but had no effect on apoptosis triggered by IFN-α. The potentiating effect of rapamycin on apoptosis in H929 cells was associated to an increase in basal and IFN-α-induced Bim levels. Our results indicate that IFN-α causes apoptosis in myeloma cells through a moderate triggering of the mitochondrial route initiated by Bim and that mTOR inhibitors may be useful in IFN-α maintenance therapy of certain MM patients.
URIhttp://hdl.handle.net/10261/61158
DOI10.1016/j.cellsig.2006.10.009
Identifiersdoi: 10.1016/j.cellsig.2006.10.009
issn: 0898-6568
Appears in Collections:(IBMCC) Artículos
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