Hassan Ghmkin, Afify Said M, Du Juan, Nawara Hend M, Sheta Mona, Monzur Sadia, Zahra Maram H, Abu Quora Hagar A, Mansour Hager, El-Ghlban Samah, Uesaki Ryo, Seno Akimasa, Seno Masaharu
Laboratory of Nano-Biotechnology, Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; Department of Genomic Oncology and Oral Medicine, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima 734-8553, Japan; Department of Microbiology and Biochemistry, Faculty of Pharmacy, Damascus University, Damascus, Syria.
Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Shebin El Koum-Menoufia 32511, Egypt.
Biochem Biophys Res Commun. 2021 Oct 23;583:49-55. doi: 10.1016/j.bbrc.2021.10.047.
Cancer stem cells (CSCs) are responsible for cancer initiation, drug resistance, and aggressive tumor phenotypes. Our lab has established a novel method to induce CSCs from induced pluripotent stem (iPS) cells in a microenvironment mimicking chronic inflammation. The converted cells acquired CSC characteristics and developed malignant tumors. Recently, we demonstrated that nonmutagenic chemical inhibitors accelerated the conversion of mouse iPS (miPS) cells into CSCs. Here, we investigated the effects of AZD-6244, a MEK1/2-specific inhibitor, on the conversion of iPS cells into CSCs. The miPS cells were cultured for one week in the presence of the conditioned medium (CM) of Lewis lung carcinoma (LLC) cells and AZD-6244, PD0325901, a pan-MEK inhibitor, or GDC-0879, a B-Raf inhibitor. As a result, AZD-6244 enhanced the conversion of iPS cells into CSCs and upregulated AKT phosphorylation as same as GDC-0879 and PD0325901. The converted cells maintained their self-renewal ability and stemness gene expression. The expression of the CSC markers CD24, CD44 and CD133 was higher in the cells cultured with MAPK inhibitors than in those cultured without MAPK inhibitors. Moreover, converted cells gained migration and invasion abilities assessed by in vitro assays. Therefore, the inhibition of MEK1/2 was found to be critical for the conversion of normal stem cells into CSCs in the tumor-inducing microenvironment.
癌症干细胞（CSCs）负责癌症的起始、耐药性和侵袭性肿瘤表型。我们实验室建立了一种新方法，可在模拟慢性炎症的微环境中从诱导多能干细胞（iPS）诱导产生CSCs。转化后的细胞获得了CSC特征并发展为恶性肿瘤。最近，我们证明非诱变化学抑制剂可加速小鼠iPS（miPS）细胞向CSCs的转化。在此，我们研究了MEK1/2特异性抑制剂AZD-6244对iPS细胞向CSCs转化的影响。将miPS细胞在Lewis肺癌（LLC）细胞的条件培养基（CM）以及AZD-6244、泛MEK抑制剂PD0325901或B-Raf抑制剂GDC-0879存在的情况下培养一周。结果，AZD-6244增强了iPS细胞向CSCs的转化，并上调了AKT磷酸化，与GDC-0879和PD0325901相同。转化后的细胞保持了自我更新能力和干性基因表达。与未用MAPK抑制剂培养的细胞相比，用MAPK抑制剂培养的细胞中CSC标志物CD24、CD44和CD133的表达更高。此外，通过体外试验评估发现转化后的细胞获得了迁移和侵袭能力。因此，发现抑制MEK1/2对于在肿瘤诱导微环境中将正常干细胞转化为CSCs至关重要。
