苯乙基异硫氰酸酯和其他活性氧诱导型抗癌剂的作用机制。
Mechanism of action of phenethylisothiocyanate and other reactive oxygen species-inducing anticancer agents.
机构信息
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas, USA.
Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas, USA.
出版信息
Mol Cell Biol. 2014 Jul;34(13):2382-95. doi: 10.1128/MCB.01602-13. Epub 2014 Apr 14.
Abstract
Reactive oxygen species (ROS)-inducing anticancer agents such as phenethylisothiocyanate (PEITC) activate stress pathways for killing cancer cells. Here we demonstrate that PEITC-induced ROS decreased expression of microRNA 27a (miR-27a)/miR-20a:miR-17-5p and induced miR-regulated ZBTB10/ZBTB4 and ZBTB34 transcriptional repressors, which, in turn, downregulate specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells. Decreased expression of miR-27a/miR-20a:miR-17-5p by PEITC-induced ROS is a key step in triggering the miR-ZBTB Sp cascade leading to downregulation of Sp TFs, and this is due to ROS-dependent epigenetic effects associated with genome-wide shifts in repressor complexes, resulting in decreased expression of Myc and the Myc-regulated miRs. Knockdown of Sp1 alone by RNA interference also induced apoptosis and decreased pancreatic cancer cell growth and invasion, indicating that downregulation of Sp transcription factors is an important common mechanism of action for PEITC and other ROS-inducing anticancer agents.
摘要
活性氧（ROS）诱导的抗癌剂，如苯乙基异硫氰酸酯（PEITC），通过激活应激途径来杀死癌细胞。在这里，我们证明了 PEITC 诱导的 ROS 降低了 microRNA 27a（miR-27a）/miR-20a:miR-17-5p 的表达，并诱导了 miR 调节的 ZBTB10/ZBTB4 和 ZBTB34 转录抑制因子，进而下调了胰腺癌细胞中的特异性蛋白（Sp）转录因子（TF）Sp1、Sp3 和 Sp4。PEITC 诱导的 ROS 降低 miR-27a/miR-20a:miR-17-5p 的表达是触发 miR-ZBTB Sp 级联反应的关键步骤，导致 Sp TF 下调，这是由于与基因组范围的抑制复合物变化相关的 ROS 依赖性表观遗传效应，导致 Myc 和 Myc 调节的 miR 表达降低。通过 RNA 干扰单独敲低 Sp1 也诱导了细胞凋亡，并降低了胰腺癌细胞的生长和侵袭，表明 Sp 转录因子的下调是 PEITC 和其他 ROS 诱导的抗癌剂的一个重要共同作用机制。
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