Selective apoptosis induction by the cancer chemopreventive agent N-(4-hydroxyphenyl)retinamide is achieved by modulating mitochondrial bioenergetics in premalignant and malignant human prostate epithelial cells
Selective apoptosis induction by the cancer chemopreventive agent N-(4-hydroxyphenyl)retinamide is achieved by modulating mitochondrial bioenergetics in premalignant and malignant human prostate epithelial cells
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DOI：
10.1007/s10495-009-0356-4
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发表时间：
2009-07-01
期刊：
影响因子：
7.2
通讯作者：
Kepa, Jadwiga J.
中科院分区：
文献类型：
--
作者：
Hail, Numsen, Jr.;Chen, Ping;Kepa, Jadwiga J.
前列腺肿瘤的发生与转化的前列腺上皮细胞的早期代谢开关相结合，有效地增加了它们的线粒体生物能量能力。合成的类维甲酸N-（4-羟基苯基）维甲酸（4HPR）在体内抑制前列腺癌的发展，并在体外触发活性氧（ROS）依赖性前列腺癌细胞凋亡。4hpr诱导的ROS生成可能与线粒体生物能量学有关，并且是体外转化前列腺上皮细胞诱导凋亡所必需的，这将为4hpr介导的前列腺癌体内化学预防提供前瞻性的机制基础。我们通过比较4HPR对人前列腺癌前上皮细胞PWR-1E和恶性前列腺上皮细胞DU-145的影响来研究这一原理。4HPR促进了PWR-1E和DU-145细胞的剂量和/或时间依赖性的凋亡诱导，这一过程之前并依赖于线粒体ROS生成的增加。在这方面，PWR-1E细胞比DU-145细胞更敏感，它们消耗的氧气大约是DU-145细胞的两倍，这表明氧化磷酸化在癌前细胞中更高。有趣的是，在PWR-1E细胞的培养基中增加[Ca2+]会降低其增殖能力、线粒体生物能量能力和4HPR的细胞毒性作用。相应地，DU-145细胞的呼吸缺陷衍生物（即缺乏线粒体DNA的rho(0)细胞）对4hpr诱导的ROS产生和凋亡具有明显的抗性。总之，这些观察结果表明，线粒体生物能量的减少保护PWR-1E和DU-145细胞免受4HPR的细胞毒性作用，并支持氧化磷酸化是转化的人前列腺上皮细胞中4HPR凋亡信号传导的重要决定因素的概念。
Prostate tumorigenesis is coupled with an early metabolic switch in transformed prostate epithelial cells that effectively increases their mitochondrial bioenergetic capacity. The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) inhibits prostate cancer development in vivo, and triggers reactive oxygen species (ROS)-dependent prostate cancer cell apoptosis in vitro. The possibility that 4HPR-induced ROS production is associated with mitochondrial bioenergetics and required for apoptosis induction in transformed prostate epithelial cells in vitro would advocate a prospective mechanistic basis for 4HPR-mediated prostate cancer chemoprevention in vivo. We investigated this tenet by comparing and contrasting 4HPR's effects on premalignant PWR-1E and malignant DU-145 human prostate epithelial cells. 4HPR promoted a dose- and/or time-dependent apoptosis induction in PWR-1E and DU-145 cells, which was preceded by and dependent on an increase in mitochondrial ROS production. In this regard, the PWR-1E cells were more sensitive than the DU-145 cells, and they consumed roughly twice as much oxygen as the DU-145 cells suggesting oxidative phosphorylation was higher in the premalignant cells. Interestingly, increasing the [Ca2+] in the culture medium of the PWR-1E cells attenuated their proliferation as well as their mitochondrial bioenergetic capacity and 4HPR's cytotoxic effects. Correspondingly, the respiration-deficient derivatives (i.e., rho(0) cells lacking mitochondrial DNA) of DU-145 cells were markedly resistant to 4HPR-induced ROS production and apoptosis. Together, these observations implied that the reduction of mitochondrial bioenergetics protected PWR-1E and DU-145 cells against the cytotoxic effects of 4HPR, and support the concept that oxidative phosphorylation is an essential determinant in 4HPR's apoptogenic signaling in transformed human prostate epithelial cells.