Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune, Dr Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India.
J Mater Chem B. 2020 May 21;8(19):4259-4266. doi: 10.1039/d0tb00408a. Epub 2020 Apr 14.
The presence of the same proteins at different sub-cellular locations with completely different functions adds to the complexity of signalling pathways in cancer. Subsequently, it becomes indispensable to understand the diverse critical roles of these proteins based on their spatial distribution for the development of improved cancer therapeutics. To address this, in this work, we report the development of endoplasmic reticulum (ER) and mitochondria targeted nanoscale particles to spatially impair anti-apoptotic Bcl-2 protein in these organelles in HeLa cervical cancer cells. Confocal microscopy and gel electrophoresis confirmed that these nanoparticles selectively home into ER and mitochondria and inhibited Bcl-2 localized there. Interestingly, Bcl-2 inhibition in ER induced ER stress leading to autophagy, whereas inhibition of Bcl-2 in mitochondria leads to mitochondrial damage and programmed cell death (apoptosis) in HeLa cells. These nanoscale platforms can be further explored as chemical biology tools to decipher the location-function relationship of proteins towards next generation cancer therapeutics.
相同的蛋白质在不同的亚细胞位置具有完全不同的功能，这增加了癌症信号通路的复杂性。因此，根据这些蛋白质的空间分布理解其多样化的关键作用对于开发改进的癌症治疗方法是必不可少的。为了解决这个问题，在这项工作中，我们报告了内质网 (ER) 和线粒体靶向纳米颗粒的开发，以在 HeLa 宫颈癌细胞中空间上破坏这些细胞器中的抗凋亡 Bcl-2 蛋白。共聚焦显微镜和凝胶电泳证实，这些纳米颗粒选择性地进入 ER 和线粒体，并抑制那里的 Bcl-2 定位。有趣的是，ER 中的 Bcl-2 抑制诱导 ER 应激导致自噬，而线粒体中 Bcl-2 的抑制导致线粒体损伤和 HeLa 细胞中的程序性细胞死亡（凋亡）。这些纳米平台可以进一步探索作为化学生物学工具，以破译蛋白质的位置-功能关系，为下一代癌症治疗方法提供信息。
