TY - JOUR
T1 - MEK1/2 is a bottleneck that induces cancer stem cells to activate the PI3K/AKT pathway
AU - Hassan, Ghmkin
AU - Afify, Said M.
AU - Du, Juan
AU - Nawara, Hend M.
AU - Sheta, Mona
AU - Monzur, Sadia
AU - Zahra, Maram H.
AU - Abu Quora, Hagar A.
AU - Mansour, Hager
AU - El-Ghlban, Samah
AU - Uesaki, Ryo
AU - Seno, Akimasa
AU - Seno, Masaharu
N1 - Funding Information:
This work was supported by the iPS-CSC Project at Okayama University (to MS) and Grant-in-Aid for Early Career Scientists from MEXT , Japan ( 18K15243 to AS).
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/12/17
Y1 - 2021/12/17
N2 - 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.
AB - 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.
KW - Cancer stem cells
KW - MEK/ERK pathway
KW - PI3K/AKT pathway
KW - Tumor-inducing microenvironment
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U2 - 10.1016/j.bbrc.2021.10.047
DO - 10.1016/j.bbrc.2021.10.047
M3 - Article
C2 - 34735879
AN - SCOPUS:85117937881
SN - 0006-291X
VL - 583
SP - 49
EP - 55
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
ER -
