MEK1/2 is a bottleneck that induces cancer stem cells to activate the PI3K/AKT pathway

Ghmkin Hassan; Said M Afify; Juan Du; Hend M Nawara; Mona Sheta; Sadia Monzur; Maram H Zahra; Hagar A Abu Quora; Hager Mansour; Samah El-Ghlban; Ryo Uesaki; Akimasa Seno; Masaharu Seno

doi:10.1016/j.bbrc.2021.10.047

MEK1/2 is a bottleneck that induces cancer stem cells to activate the PI3K/AKT pathway

Biochem Biophys Res Commun. 2021 Oct 23:583:49-55. doi: 10.1016/j.bbrc.2021.10.047. Online ahead of print.

Authors

Ghmkin Hassan¹, Said M Afify², Juan Du³, Hend M Nawara⁴, Mona Sheta⁵, Sadia Monzur⁴, Maram H Zahra⁴, Hagar A Abu Quora⁶, Hager Mansour⁴, Samah El-Ghlban², Ryo Uesaki⁴, Akimasa Seno⁷, Masaharu Seno⁸

Affiliations

¹ 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.
² Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Shebin El Koum-Menoufia 32511, Egypt.
³ Department of Cancer Institute, Shanxi Provincial Cancer Hospital, Taiyuan, PR China.
⁴ 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.
⁵ 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 Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt.
⁶ 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; Cytology, Histology and Histochemistry, Zoology Department, Faculty of Science, Menoufia University, Menoufia 32511, Egypt.
⁷ 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; The Laboratory of Natural Food and Medicine, Co Ltd, Okayama 700-8530, Japan.
⁸ 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. Electronic address: mseno@okayama-u.ac.jp.

PMID: 34735879
DOI: 10.1016/j.bbrc.2021.10.047

Abstract

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.

Keywords: Cancer stem cells; MEK/ERK pathway; PI3K/AKT pathway; Tumor-inducing microenvironment.