NSC-640358 acts as RXRα ligand to promote TNFα-mediated apoptosis of cancer cell.
NSC-640358 acts as RXRα ligand to promote TNFα-mediated apoptosis of cancer cell.
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NSC-640358 作为 RXR α 配体促进 TNF α 介导的癌细胞凋亡
DOI：
10.1007/s13238-015-0178-9
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发表时间：
2015-09
期刊：
影响因子：
21.1
通讯作者：
Zhou H
中科院分区：
文献类型：
--
作者：
Chen F;Chen J;Lin J;Cheltsov AV;Xu L;Chen Y;Zeng Z;Chen L;Huang M;Hu M;Ye X;Zhou Y;Wang G;Su Y;Zhang L;Zhou F;Zhang XK;Zhou H
维甲酸X受体α（Retinoid X receptor α，RXRα）及其N端截短型tRXRα在肿瘤发生中起重要作用，而RXRα配体通过靶向和调节RXRα和tRXRα的致瘤作用而具有潜在的抗癌活性。NSC-640358（N-6）是一种噻唑基-吡唑衍生物，可作为RXRα的选择性配体促进TNFα介导的肿瘤细胞凋亡。N-6与RXRα结合并抑制RXRα同源二聚体和RXRα/TR 3异源二聚体的反式激活。使用突变分析和计算研究，我们确定了RXRα中的Arg 316，对于9-cis-维甲酸结合和激活RXRα反式激活是必需的，对于N-6的拮抗作用不是必需的，而Trp 305和Phe 313通过与N-6形成额外的π-π堆积相互作用而对N-6与RXRα结合至关重要，表明N-6的独特RXRα结合模式。N-6通过与RXRα-LBD的配体结合口袋结合来抑制TR 3刺激的Gal 4-DBD-RXRα-LBD的反式激活，这表明通过使用小分子靶向其相互作用伴侣RXRα来间接调节TR 3活性的策略。对于其生理活性，我们表明N-6强烈抑制肿瘤坏死因子α（TNFα）诱导的AKT活化，并以RXRα/tRXRα依赖性方式刺激TNFα介导的癌细胞凋亡。N-6对TNFα诱导的tRXRα/p85α复合物形成的抑制作用表明N-6靶向tRXRα以抑制TNFα诱导的AKT活化并诱导癌细胞凋亡。总之，我们的数据说明了一种新的RXRα配体，具有独特的RXRα结合模式，能够间接调节TR 3活性，并通过靶向RXRα/tRXRα诱导TNFα介导的癌细胞凋亡。
Retinoid X receptor α (RXRα) and its N-terminally truncated version tRXRα play important roles in tumorigenesis, while some RXRα ligands possess potent anti-cancer activities by targeting and modulating the tumorigenic effects of RXRα and tRXRα. Here we describe NSC-640358 (N-6), a thiazolyl-pyrazole derived compound, acts as a selective RXRα ligand to promote TNFα-mediated apoptosis of cancer cell. N-6 binds to RXRα and inhibits the transactivation of RXRα homodimer and RXRα/TR3 heterodimer. Using mutational analysis and computational study, we determine that Arg316 in RXRα, essential for 9-cis-retinoic acid binding and activating RXRα transactivation, is not required for antagonist effects of N-6, whereas Trp305 and Phe313 are crucial for N-6 binding to RXRα by forming extra π–π stacking interactions with N-6, indicating a distinct RXRα binding mode of N-6. N-6 inhibits TR3-stimulated transactivation of Gal4-DBD-RXRα-LBD by binding to the ligand binding pocket of RXRα-LBD, suggesting a strategy to regulate TR3 activity indirectly by using small molecules to target its interacting partner RXRα. For its physiological activities, we show that N-6 strongly inhibits tumor necrosis factor α (TNFα)-induced AKT activation and stimulates TNFα-mediated apoptosis in cancer cells in an RXRα/tRXRα dependent manner. The inhibition of TNFα-induced tRXRα/p85α complex formation by N-6 implies that N-6 targets tRXRα to inhibit TNFα-induced AKT activation and to induce cancer cell apoptosis. Together, our data illustrate a new RXRα ligand with a unique RXRα binding mode and the abilities to regulate TR3 activity indirectly and to induce TNFα-mediated cancer cell apoptosis by targeting RXRα/tRXRα.
影响因子：
3.7
作者：
Shiryaev SA;Cheltsov AV;Strongin AY
通讯作者：
Strongin AY