Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Biochemistry Building, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy.
Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via del Vespro 129, 90127 Palermo, Italy.
Int J Mol Sci. 2020 Oct 30;21(21):8135. doi: 10.3390/ijms21218135.
Organotin compounds represent potential cancer therapeutics due to their pro-apoptotic action. We recently synthesized the novel organotin ferulic acid derivative tributyltin (IV) ferulate (TBT-F) and demonstrated that it displays anti-tumor properties in colon cancer cells related with autophagic cell death. The purpose of the present study was to elucidate the mechanism of TBT-F action in colon cancer cells. We specifically show that TBT-F-dependent autophagy is determined by a rapid generation of reactive oxygen species (ROS) and correlated with endoplasmic reticulum (ER) stress. TBT-F evoked nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated antioxidant response and Nrf2 silencing by RNA interference markedly increased the anti-tumor efficacy of the compound. Moreover, as a consequence of ROS production, TBT-F increased the levels of glucose regulated protein 78 (Grp78) and C/EBP homologous protein (CHOP), two ER stress markers. Interestingly, Grp78 silencing produced significant decreasing effects on the levels of the autophagic proteins p62 and LC3-II, while only p62 decreased in CHOP-silenced cells. Taken together, these results indicate that ROS-dependent ER stress and autophagy play a major role in the TBT-F action mechanism in colon cancer cells and open a new perspective to consider the compound as a potential candidate for colon cancer treatment.
有机锡化合物由于其促凋亡作用而成为有潜力的癌症治疗药物。我们最近合成了新型有机锡阿魏酸衍生物三丁基锡（IV）阿魏酸酯（TBT-F），并证明它在结肠癌细胞中具有与自噬细胞死亡相关的抗肿瘤特性。本研究的目的是阐明 TBT-F 在结肠癌细胞中的作用机制。我们特别表明，TBT-F 依赖性自噬是由活性氧（ROS）的快速产生决定的，并与内质网（ER）应激有关。TBT-F 引发核因子红细胞 2 相关因子 2（Nrf2）介导的抗氧化反应，RNA 干扰沉默 Nrf2 显著增加了该化合物的抗肿瘤功效。此外，由于 ROS 的产生，TBT-F 增加了葡萄糖调节蛋白 78（Grp78）和 C/EBP 同源蛋白（CHOP）的水平，这两种 ER 应激标志物。有趣的是，Grp78 沉默对自噬蛋白 p62 和 LC3-II 的水平产生了显著的降低作用，而 CHOP 沉默细胞中仅 p62 降低。总之，这些结果表明，ROS 依赖性 ER 应激和自噬在 TBT-F 对结肠癌细胞的作用机制中起主要作用，并为将该化合物视为结肠癌治疗的潜在候选药物开辟了新的视角。
