Lee DaeYong, Lee Soo-Hwan, Noh Ilkoo, Oh Eonju, Ryu Hyunil, Ha JongHoon, Jeong SeongDong, Yoo Jisang, Jeon Tae-Joon, Yun Chae-Ok, Kim Yeu-Chun
Department of Chemical and Biomolecular Engineering Korea Advanced Institute of Science and Technology (KAIST) Daejeon 34141 Republic of Korea.
Department of Bioengineering College of Engineering Hanyang University Seoul 04763 Republic of Korea.
Adv Sci (Weinh). 2019 May 24;6(14):1801995. doi: 10.1002/advs.201801995. eCollection 2019 Jul 17.
Perturbation of potassium homeostasis can affect various cell functions and lead to the onset of programmed cell death. Although ionophores have been intensively used as an ion homeostasis disturber, the mechanisms of cell death are unclear and the bioapplicability is limited. In this study, helical polypeptide-based potassium ionophores are developed to induce endoplasmic reticulum (ER) stress-mediated apoptosis. The polypeptide-based potassium ionophores disturb ion homeostasis and then induce prolonged ER stress in the cells. The ER stress results in oxidative environments that accelerate the activation of mitochondria-dependent apoptosis. Moreover, ER stress-mediated apoptosis is triggered in a tumor-bearing mouse model that suppresses tumor proliferation. This study provides the first evidence showing that helical polypeptide-based potassium ionophores trigger ER stress-mediated apoptosis by perturbation of potassium homeostasis.
钾离子稳态的扰动会影响各种细胞功能，并导致程序性细胞死亡的发生。尽管离子载体已被广泛用作离子稳态干扰剂，但其细胞死亡机制尚不清楚，生物适用性也有限。在本研究中，开发了基于螺旋多肽的钾离子载体以诱导内质网（ER）应激介导的细胞凋亡。基于多肽的钾离子载体扰乱离子稳态，进而在细胞中诱导长时间的内质网应激。内质网应激导致氧化环境，加速线粒体依赖性细胞凋亡的激活。此外，在抑制肿瘤增殖的荷瘤小鼠模型中触发了内质网应激介导的细胞凋亡。本研究提供了首个证据，表明基于螺旋多肽的钾离子载体通过扰乱钾离子稳态触发内质网应激介导的细胞凋亡。
