Dihydroorotate dehydrogenase is required for N-(4-hydroxyphenyl)retinamide-induced reactive oxygen species production and apoptosis.
Dihydroorotate dehydrogenase is required for N-(4-hydroxyphenyl)retinamide-induced reactive oxygen species production and apoptosis.
复制标题
DOI：
10.1016/j.freeradbiomed.2010.04.006
复制
发表时间：
2010-07-01
影响因子：
7.4
通讯作者：
Shearn, Colin
中科院分区：
文献类型：
--
作者：
Hail, Numsen, Jr.;Chen, Ping;Kepa, Jadwiga J.;Bushman, Lane R.;Shearn, Colin
关键词：
合成类维生素A N-（4-羟基苯基）维A酰胺（4 HPR）在体内表现出抗癌活性，并在体外引发转化细胞的凋亡。因此，细胞凋亡诱导被认为是4 HPR的癌症预防和治疗作用的机制基础。4 HPR诱导的凋亡通常在转化细胞中产生活性氧（ROS）之前并依赖于活性氧的产生。除了线粒体电子传递链或质膜NADPH氧化酶复合物的可能参与外，几乎没有证据存在，这将确定转化细胞中4 HPR诱导的ROS产生的主要位点。在这里，我们调查的作用，二氢乳清酸脱氢酶（DHODH，与线粒体电子传递链和从头嘧啶合成所需的酶）在4 HPR诱导的ROS生产和伴随的细胞凋亡转化的皮肤和前列腺上皮细胞。在癌前前列腺上皮细胞和恶性皮肤角质形成细胞中，通过化学抑制剂特立氟胺抑制DHODH活性或通过RNA干扰减少DHODH蛋白表达显著降低了4 HPR诱导的ROS生成和细胞凋亡。相反，缺乏DHODH表达的结肠癌细胞对4 HPR的促氧化和细胞毒性作用具有显著抗性。总之，这些结果强烈暗示DHODH在4 HPR诱导的ROS产生和细胞凋亡中。
The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) exhibits anticancer activity in vivo and triggers apoptosis in transformed cells in vitro. Thus, apoptosis induction is acknowledged as a mechanistic underpinning for 4HPR's cancer preventive and therapeutic effects. Apoptosis induction by 4HPR is routinely preceded by and dependent on the production of reactive oxygen species (ROS) in transformed cells. Very little evidence exists outside the possible involvement of the mitochondrial electron transport chain or the plasma membrane NADPH oxidase complex, which would pinpoint the predominant site of 4HPR-induced ROS production in transformed cells. Here, we investigated the role of dihydroorotate dehydrogenase (DHODH, an enzyme associated with the mitochondrial electron transport chain and required for de novo pyrimidine synthesis) in 4HPR-induced ROS production and attendant apoptosis in transformed skin and prostate epithelial cells. In premalignant prostate epithelial cells and malignant cutaneous keratinocytes the suppression of DHODH activity by the chemical inhibitor teriflunomide or the reduction in DHODH protein expression by RNA interference markedly reduced 4HPR-induced ROS generation and apoptosis. Conversely, colon carcinoma cells that lacked DHODH expression were markedly resistant to the prooxidant and cytotoxic effects of 4HPR. Together, these results strongly implicate DHODH in 4HPR-induced ROS production and apoptosis.
登录
查看更多内容
影响因子：
8
作者：
Cuperus, Roos;Leen, Rene;Tytgat, Godelieve A. M.;Caron, Huib N.;van Kuilenburg, Andre B. P.
通讯作者：
van Kuilenburg, Andre B. P.
影响因子：
5.7
作者：
Baumann, Philipp;Mandl-Weber, Sonja;Schmidmaier, Ralf
通讯作者：
Schmidmaier, Ralf
影响因子：
4.8
作者：
Hail, N;Lotan, R
通讯作者：
Lotan, R
影响因子：
7.2
作者：
Hail, Numsen, Jr.;Chen, Ping;Kepa, Jadwiga J.
通讯作者：
Kepa, Jadwiga J.
影响因子：
3.8
作者：
Fletcher, CV;Kawle, SP;Remmel, RP
通讯作者：
Remmel, RP