Glutathione depletion up-regulates Bcl-2 in BSO-resistant cells.
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.
Dipartimento di Biologia, Universita' di Roma Tor Vergata, Rome, Italy.
Maria
M
D'Alessio
Claudia
C
Cerella
Carla
C
Amici
Caterina
C
Pesce
Simona
S
Coppola
Claudia
C
Fanelli
Milena
M
De Nicola
Silvia
S
Cristofanon
Giovanna
G
Clavarino
Antonio
A
Bergamaschi
Andrea
A
Magrini
Giampiero
G
Gualandi
Lina
L
Ghibelli
D017209:Apoptosis / Q000187:drug effects; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects*
D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D019328:Buthionine Sulfoximine; D005978:Glutathione