RRC ID 60953
Author Du J, Xu Y, Sasada S, Oo AKK, Hassan G, Mahmud H, Khayrani AC, Alam MJ, Kumon K, Uesaki R, Afify SM, Mansour HM, Nair N, Zahra MH, Seno A, Okada N, Chen L, Yan T, Seno M.
Title Signaling Inhibitors Accelerate the Conversion of mouse iPS Cells into Cancer Stem Cells in the Tumor Microenvironment.
Journal Sci Rep
Abstract Cancer stem cells (CSCs) are a class of cancer cells characterized by self-renewal, differentiation and tumorigenic potential. We previously established a model of CSCs by culturing mouse induced pluripotent stem cells (miPSCs) for four weeks in the presence of a conditioned medium (CM) of cancer cell lines, which functioned as the tumor microenvironment. Based on this methodology of developing CSCs from miPSCs, we assessed the risk of 110 non-mutagenic chemical compounds, most of which are known as inhibitors of cytoplasmic signaling pathways, as potential carcinogens. We treated miPSCs with each compound for one week in the presence of a CM of Lewis lung carcinoma (LLC) cells. However, one-week period was too short for the CM to convert miPSCs into CSCs. Consequently, PDO325901 (MEK inhibitor), CHIR99021 (GSK-3β inhibitor) and Dasatinib (Abl, Src and c-Kit inhibitor) were found to confer miPSCs with the CSC phenotype in one week. The tumor cells that survived exhibited stemness markers, spheroid formation and tumorigenesis in Balb/c nude mice. Hence, we concluded that the three signal inhibitors accelerated the conversion of miPSCs into CSCs. Similarly to our previous study, we found that the PI3K-Akt signaling pathway was upregulated in the CSCs. Herein, we focused on the expression of relative genes after the treatment with these three inhibitors. Our results demonstrated an increased expression of pik3ca, pik3cb, pik3r5 and pik3r1 genes indicating class IA PI3K as the responsible signaling pathway. Hence, AKT phosphorylation was found to be up-regulated in the obtained CSCs. Inhibition of Erk1/2, tyrosine kinase, and/or GSK-3β was implied to be involved in the enhancement of the PI3K-AKT signaling pathway in the undifferentiated cells, resulting in the sustained stemness, and subsequent conversion of miPSCs into CSCs in the tumor microenvironment.
Volume 10(1)
Pages 9955
Published 2020-6-22
DOI 10.1038/s41598-020-66471-2
PII 10.1038/s41598-020-66471-2
PMID 32572057
PMC PMC7308356
MeSH Animals Benzamides / pharmacology Carcinoma, Lewis Lung / metabolism* Carcinoma, Lewis Lung / pathology Cell Transformation, Neoplastic Cells, Cultured Dasatinib / pharmacology Diphenylamine / analogs & derivatives Diphenylamine / pharmacology Enzyme Inhibitors / pharmacology* Female Induced Pluripotent Stem Cells / cytology Induced Pluripotent Stem Cells / drug effects* Induced Pluripotent Stem Cells / metabolism Mice Mice, Inbred BALB C Mice, Nude Neoplastic Stem Cells / cytology Neoplastic Stem Cells / drug effects* Neoplastic Stem Cells / metabolism Phosphatidylinositol 3-Kinases / genetics Phosphatidylinositol 3-Kinases / metabolism Proto-Oncogene Proteins c-akt / genetics Proto-Oncogene Proteins c-akt / metabolism Pyridines / pharmacology Pyrimidines / pharmacology Signal Transduction* Tumor Microenvironment*
IF 3.998
Times Cited 0
Human and Animal Cells iPS-MEF-Ng-20D-17(APS0001)