Involvement of Rac in fenretinide-induced apoptosis
Involvement of Rac in fenretinide-induced apoptosis
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DOI：
10.1158/0008-5472.can-08-0031
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发表时间：
2008-06-01
期刊：
影响因子：
11.2
通讯作者：
Lotan, Reuben
中科院分区：
文献类型：
--
作者：
Kadara, Humam;Tahara, Eiji;Lotan, Reuben
合成的类维甲酸N-（4-羟基苯基）维甲酸（4HPR）已显示出作为化学预防和治疗药物的潜力。4HPR增强活性氧（ROS）产生导致细胞凋亡的能力被认为是这些作用的可能机制。我们探索了4HPR诱导ROS涉及小GTPase ras相关C3肉毒毒素底物（Rac）的可能性，这是NADPH氧化酶复合物的一个调节亚基。人类头颈部鳞状细胞癌（HNSCC）细胞早在4HPR暴露后5分钟就被激活。此外，通过RNA干扰抑制Rac活性或沉默其表达可减少人头颈、肺癌、宫颈癌细胞和小鼠黑色素瘤细胞中ROS的生成。在HNSCC - UMSCC-22B细胞中，这种下降与4HPR诱导凋亡的减少有关。组成型活性突变体Rac的表达增加了基础和4hpr诱导的ROS生成和聚（adp -核糖）聚合酶裂解。此外，与原代Tu167-C2细胞相比，4HPR处理后的转移性DM14细胞表现出更高的Rac激活。此外，与原发癌细胞相比，转移癌细胞由于暴露于4HPR而表现出更高的ROS生成和生长抑制。这些发现表明，通过Rac激活，转移细胞对促凋亡的类维甲酸4HPR具有优先敏感性，并支持使用ros诱导剂（如4HPR）来对抗转移癌细胞。
The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) has shown potential as a chemopreventive and therapeutic agent. The ability of 4HPR to enhance production of reactive oxygen species (ROS) leading to apoptosis has been suggested as a possible mechanism underlying these effects. We explored the possibility that ROS induction by 4HPR involves the small GTPase Ras-related C3 botulinum toxin substrate (Rac), a regulatory subunit of the NADPH oxidase complex. Rac was activated in human head and neck squamous cell carcinoma (HNSCC) cells as early as 5 minutes following 4HPR exposure. Moreover, inhibition of Rac activity or silencing of its expression by RNA interference decreased ROS generation in human head and neck, lung, and cervical cancer cells and murine melanoma cells. In HNSCC UMSCC-22B cells, this decrease correlated with reduction in apoptosis induction by 4HPR. Expression of a constitutive active mutant Rac increased basal and 4HPR-induced ROS generation and poly(ADP-ribose) polymerase cleavage. In addition, the metastatic DM14 cells exhibited higher Rac activation following 4HPR treatment compared with the primary Tu167-C2 cells. Furthermore, the metastatic cancer cells tested exhibited higher ROS generation and growth inhibition due to 4HPR exposure compared with their primary cancer cell counterparts. These findings show a preferential susceptibility of metastatic cells to the proapoptotic retinoid 4HPR through Rac activation and support the use of ROS-inducing agents such as 4HPR against metastatic cancer cells.