beta-Lapachone-induced apoptosis in human prostate cancer cells: involvement of NQO1/xip3.
Exp Cell Res
; 267(1): 95-106, 2001 Jul 01.
Article
en En
| MEDLINE
| ID: mdl-11412042
ABSTRACT
beta-Lapachone (beta-lap) induces apoptosis in various cancer cells, and its intracellular target has recently been elucidated in breast cancer cells. Here we show that NAD(P)Hquinone oxidoreductase (NQO1/xip3) expression in human prostate cancer cells is a key determinant for apoptosis and lethality after beta-lap exposures. beta-Lap-treated, NQO1-deficient LNCaP cells were significantly more resistant to apoptosis than NQO1-expressing DU-145 or PC-3 cells after drug exposures. Formation of an atypical 60-kDa PARP cleavage fragment in DU-145 or PC-3 cells was observed after 10 microM beta-lap treatment and correlated with apoptosis. In contrast, LNCaP cells required 25 microM beta-lap to induce similar responses. Atypical PARP cleavage in beta-lap-treated cells was not affected by 100 microM zVAD-fmk; however, coadministration of dicoumarol, a specific inhibitor of NQO1, reduced beta-lap-mediated cytotoxicity, apoptosis, and atypical PARP cleavage in NQO1-expressing cells. Dicoumarol did not affect the more beta-lap-resistant LNCaP cells. Stable transfection of LNCaP cells with NQO1 increased their sensitivity to beta-lap, enhancing apoptosis compared to parental LNCaP cells or vector-alone transfectants. Dicoumarol increased survival of beta-lap-treated NQO1-expressing LNCaP transfectants. NQO1 activity, therefore, is a key determinant of beta-lap-mediated apoptosis and cytotoxicity in prostate cancer cells.
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Colección:
01-internacional
Asunto principal:
Neoplasias de la Próstata
/
Naftoquinonas
/
NAD(P)H Deshidrogenasa (Quinona)
/
Apoptosis
/
Antibióticos Antineoplásicos
Límite:
Humans
/
Male
Idioma:
En
Revista:
Exp Cell Res
Año:
2001
Tipo del documento:
Article
País de afiliación:
Estados Unidos