Proapoptotic ability of oncogenic H-Ras to facilitate apoptosis induced by histone deacetylase inhibitors in human cancer cells
Proapoptotic ability of oncogenic H-Ras to facilitate apoptosis induced by histone deacetylase inhibitors in human cancer cells
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DOI：
10.1158/1535-7163.mct-06-0586
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发表时间：
2007-03-01
影响因子：
5.7
通讯作者：
Wang, Hwa-Chain Robert
中科院分区：
文献类型：
--
作者：
Choudhary, Shambhunath;Wang, Hwa-Chain Robert
超过35%的人类膀胱癌与致癌的H-Ras激活有关。除了致瘤能力外，致癌的H-Ras还具有一种新的促凋亡能力，可以促进组蛋白去乙酰化酶抑制剂（HDACI）诱导细胞凋亡。HDACIs是一类新型抗癌药物，对转化细胞具有高度的细胞毒性。为了了解HDACIs对转化细胞的选择性与促癌性H-Ras促进hdaci诱导细胞凋亡的促凋亡能力之间的联系，我们将促癌性H-Ras引入膀胱J82癌细胞，模拟H-Ras基因在肿瘤发展过程中的激活。致瘤性H-Ras的表达促进J82细胞获得突变能力。同时，致癌H-Ras增加了J82细胞对hdac的敏感性，包括FR901228和trichostatin A，以诱导细胞凋亡。FR901228在致瘤性h - ras表达的J82细胞中对caspase通路、B-Raf和细胞外信号调节激酶通路、p21 （Cip1）和p27（Kip1）以及核心组蛋白含量的调控不同于亲本J82细胞，从而增加了诱导选择性凋亡的易感性。我们的研究结果表明，hdac激活了致癌H-Ras的促凋亡能力，这表明这类新型抗癌药物在控制已进展为获得致癌H-Ras的人类膀胱癌方面具有潜在的治疗价值。
More than 35% of human urinary bladder cancers involve oncogenic H-Ras activation. In addition to tumorigenic ability, oncogenic H-Ras possesses a novel proapoptotic ability to facilitate the induction of apoptosis by histone deacetylase inhibitors (HDACI). HDACIs are a new class of anticancer agents and are highly cytotoxic to transformed cells. To understand the connection between the selectivity of HDACIs on transformed cells and the proapoptotic ability of oncogenic H-Ras to facilitate HDACI-induced apoptosis, we introduced oncogenic H-Ras into urinary bladder J82 cancer cells to mimic an acquisition of the H-ras gene activation in tumor development. Expression of oncogenic H-Ras promoted J82 cells to acquire turnorigenic ability. Meanwhile, oncogenic H-Ras increased susceptibility of J82 cells to HDACIs, including FR901228 and trichostatin A, for inducing apoptosis. The caspase pathways, the B-Raf and extracellular signal-regulated kinase pathway, p21 (Cip1) and p27(Kip1), and core histone contents are regulated differently by FR901228 in oncogenic H-Ras-expressed J82 cells than their counterparts in parental J82 cells, contributing to the increased susceptibility to the induction of selective apoptosis. Our results lead us to a suggestion that HDACIs activate the proapoptotic ability of oncogenic H-Ras, indicating a potential therapeutic value of this new class of anticancer agents in the control of human urinary bladder cancer that has progressed to acquire oncogenic H-Ras.