N-(4-hydroxyphenyl)retinamide induces apoptosis in human retinal pigment epithelial cells: retinoic acid receptors regulate apoptosis, reactive oxygen species generation, and the expression of heme oxygenase-1 and Gadd153.
N-(4-hydroxyphenyl)retinamide induces apoptosis in human retinal pigment epithelial cells: retinoic acid receptors regulate apoptosis, reactive oxygen species generation, and the expression of heme oxygenase-1 and Gadd153.
复制标题
N-(4-羟苯基)retinamide 诱导人视网膜色素上皮细胞凋亡：视黄酸受体调节细胞凋亡、活性氧的产生以及血红素加氧酶-1 和 Gadd153 的表达。
DOI：
10.1002/jcp.20774
复制
发表时间：
2006
影响因子：
5.6
通讯作者：
Wiggert,Barbara
中科院分区：
文献类型：
--
作者：
Samuel,William;Kutty,RKrishnan;Nagineni,Sahrudaya;Vijayasarathy,Camasamudram;Chandraratna,RoshanthaAS;Wiggert,Barbara
N-(4-hydroxyphenyl) retinamide (4HPR, fenretinide), a retinoic acid (RA) derivative and a potential cancer preventive agent, is known to exert its chemotherapeutic effects in cancer cells through induction of apoptosis. Earlier work from our laboratory has shown that relatively low concentrations of 4HPR induce neuronal differentiation of cultured human retinal pigment epithelial (ARPE-19) cells (Chen et al., 2003, J Neurochem 84: 972–981). However, at higher concentrations of 4HPR, these cells showed morphological changes including cell shrinkage and cell death. Here we demonstrate that ARPE-19 cells treated with 4HPR exhibit a dose-and time-dependent induction of apoptosis as evidenced by morphological changes, mono-and oligonucleosome generation, and increased activity of caspases 2 and 3. The 4HPR-induced apoptosis as well as the activation of caspases 2 and 3 were blocked by both retinoic acid receptors (RAR) pan-antagonists, AGN193109 and AGN194310, and by an RARa-specific antagonist AGN194301. 4HPR treatment also increased reactive oxygen species (ROS) generation in ARPE-19 cells in a timedependent manner as determined from the oxidation of 20, 70-dichlorofluorescin. In addition, the increase in the expression of heme oxygenase-1 (HO-1), a stress response protein, and the growth arrest and DNA damage-inducible transcription factor 153 (Gadd153) in response to the ROS generation were also blocked by these receptor antagonists. Pyrrolidine dithiocarbamate (PDTC), a free-radical scavenger, inhibited 4HPR-induced ROS generation, the expression of its downstream mediator, Gadd153, and apoptosis in the pretreated cells. Therefore, our results, clearly demonstrate that 4HPR induces apoptosis in ARPE-19 cells and that RARs mediate this process by regulating ROS generation as well as the expression of Gadd153 and HO-1. J. Cell. Physiol. 209: 854–865, 2006. Published 2006 Wiley-Liss, Inc.{N-(4-hydroxyphenyl) retinamide (4HPR, fenretinide), a synthetic derivative of all-trans retinoic acid (RA) and a chemotherapeutic agent, is known to induce apoptosis in number of cancer cell lines (Lotan, 1995; Ulukaya and Wood, 1999; Malone et al., 2003). At present, the cellular and molecular mechanisms by which 4HPR induces apoptosis are not clearly understood. However, multiple and distinct pathways are thought to contribute to this process. Several studies have shown the involvement of retinoic acid receptors (RAR), members of the steroid and thyroid hormone superfamily that mediate the biological and molecular effects of retinoids, in mediating the apoptosis induced by 4HPR in various cell types (Swisshelm et al., 1994; Sabichi et al., 1998; Pergolizzi et al., 1999). There is also compelling evidence supporting the role of reactive oxygen species (ROS) in 4HPR-induced apoptosis (Delia et al., 1997; Oridate et al., 1997). A rapid and sustained induction of growth arrest and DNA damage-inducible transcription factor 153 (Gadd153), both at the mRNA and protein level, in response to ROS generation is thought to play a key role in the apoptotic pathway induced by 4HPR (Kim et al., 2002; Lengwehasatit and Dickson, 2002; Xia et al., 2002).
