β-Lapachone-induced apoptosis in human prostate cancer cells:: Involvement of NQO1/xip3
β-Lapachone-induced apoptosis in human prostate cancer cells:: Involvement of NQO1/xip3
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DOI：
10.1006/excr.2001.5234
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发表时间：
2001-07-01
影响因子：
3.7
通讯作者：
Boothman, DA
中科院分区：
文献类型：
--
作者：
Planchon, SM;Pink, JJ;Boothman, DA
β-拉帕酮（β-lap）诱导多种癌细胞的凋亡，其细胞内靶点最近在乳腺癌细胞中得到阐明。在此，我们表明NAD（P）H：醌氧化还原酶（NQO 1/xip 3）在人前列腺癌细胞中的表达是β-lap暴露后凋亡和致死的关键决定因素。在药物暴露后，经β-lap处理的NQO 1缺陷型LNCaP细胞比表达NQO 1的DU-145或PC-3细胞对凋亡的抗性显著更强。在10 μ M β-lap处理后，在DU-145或PC-3细胞中观察到非典型60-kDa PARP切割片段的形成，并且与凋亡相关。相反，LNCaP细胞需要25 μ M β-lap才能诱导类似的反应。β-lap处理细胞中的非典型PARP切割不受100 μ M zVAD-fmk的影响;然而，同时给予双香豆素（NQO 1的特异性抑制剂）可减少β-lap介导的细胞毒性、细胞凋亡和NQO 1表达细胞中的非典型PARP切割。双香豆素不影响更具有β-lap抗性的LNCaP细胞。与亲本LNCaP细胞或单独的载体转染子相比，用NQO 1稳定转染LNCaP细胞增加了它们对β-lap的敏感性，增强了细胞凋亡。双香豆素增加β-lap处理的NQO 1表达LNCaP转染子的存活，因此，NQO 1活性是前列腺癌细胞中β-lap介导的细胞凋亡和细胞毒性的关键决定因素。(C)北京：科学出版社.
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)H:quinone 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 muM beta -lap treatment and correlated with apoptosis, In contrast, LNCaP cells required 25 muM beta -lap to induce similar responses. Atypical PARP cleavage in beta -lap-treated cells was not affected by 100 muM 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. (C) 2001 Academic Press.