Glutathione depletion by inhibition of its synthesis with buthionine sulfoximine (BSO) is a focus of the current research in antitumor therapy, BSO being used as chemosensitizer. We had previously shown that two human tumor cell lines (U937 and HepG2) survive to treatment with BSO: BSO can elicit an apoptotic response, but the apoptotic process is aborted after cytochrome c release and before caspase activation, suggesting the development of an adaptive response (FASEB J., 1999, 13, 2031-2036). Here, we investigate the mechanisms of such an adaptation. We found that following BSO, U937 up-regulate Bcl-2 mRNA and protein levels, by a mechanism possibly involving NF-kappaB transcription factor; the increase in protein level is limited by a rapid decay of Bcl-2 in BSO-treated cells, suggesting that redox imbalance speeds up Bcl-2 turnover. BSO-dependent Bcl-2 up-regulation is associated with the ability to survive to BSO. Indeed, 1) its abrogation by CAPE or protein synthesis inhibition sensitizes U937 to BSO; 2) in a panel of four tumor lines, BSO-resistant (U937, HepG2, and HGB1) but not BSO-sensitive (BL41) cells can up-regulate Bcl-2 following GSH depletion; remarkably, only the latter are chemosensitized by BSO.

D'Alessio, M., Cerella, C., Amici, C., Pesce, C.d., Coppola, S., Fanelli, C., et al. (2004). Glutathione depletion up-regulates Bcl-2 in BSO-resistant cells. THE FASEB JOURNAL, 18(13), 1609-1611 [10.1096/fj.04-1813fje].

Glutathione depletion up-regulates Bcl-2 in BSO-resistant cells

AMICI, CARLA;PESCE, CATERINA DELFINA;MAGRINI, ANDREA;GHIBELLI, LINA
2004-10-01

Abstract

Glutathione depletion by inhibition of its synthesis with buthionine sulfoximine (BSO) is a focus of the current research in antitumor therapy, BSO being used as chemosensitizer. We had previously shown that two human tumor cell lines (U937 and HepG2) survive to treatment with BSO: BSO can elicit an apoptotic response, but the apoptotic process is aborted after cytochrome c release and before caspase activation, suggesting the development of an adaptive response (FASEB J., 1999, 13, 2031-2036). Here, we investigate the mechanisms of such an adaptation. We found that following BSO, U937 up-regulate Bcl-2 mRNA and protein levels, by a mechanism possibly involving NF-kappaB transcription factor; the increase in protein level is limited by a rapid decay of Bcl-2 in BSO-treated cells, suggesting that redox imbalance speeds up Bcl-2 turnover. BSO-dependent Bcl-2 up-regulation is associated with the ability to survive to BSO. Indeed, 1) its abrogation by CAPE or protein synthesis inhibition sensitizes U937 to BSO; 2) in a panel of four tumor lines, BSO-resistant (U937, HepG2, and HGB1) but not BSO-sensitive (BL41) cells can up-regulate Bcl-2 following GSH depletion; remarkably, only the latter are chemosensitized by BSO.
ott-2004
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA
English
Con Impact Factor ISI
RNA, Messenger; Proto-Oncogene Proteins c-bcl-2; Apoptosis; Glutathione; Humans; Buthionine Sulfoximine; Cell Line, Tumor; Drug Resistance, Neoplasm; Up-Regulation; U937 Cells; Cell Survival
D'Alessio, M., Cerella, C., Amici, C., Pesce, C.d., Coppola, S., Fanelli, C., et al. (2004). Glutathione depletion up-regulates Bcl-2 in BSO-resistant cells. THE FASEB JOURNAL, 18(13), 1609-1611 [10.1096/fj.04-1813fje].
D'Alessio, M; Cerella, C; Amici, C; Pesce, Cd; Coppola, S; Fanelli, C; De Nicola, M; Cristofanon, S; Clavarino, G; Bergamaschi, A; Magrini, A; Gualand...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/34703
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