RRC ID 66084
Author Ishida K, Ito C, Ohmori Y, Kume K, Sato KA, Koizumi Y, Konta A, Iwaya T, Nukatsuka M, Kobunai T, Takechi T, Nishizuka SS.
Title Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil.
Journal Sci Rep
Abstract Drug-tolerant cancer cell subpopulations are responsible for relapse after chemotherapy. By continuously exposing the gastric cancer cell line MKN45 to 5-FU for >100 passages, we established a 5-fluorouracil (5-FU)-tolerant line, MKN45/5FU. Orthotopic xenografts of MKN45/5FU cells in the stomach of nude mice revealed that these cells had a high potential to metastasize to sites such as the liver. Levels of phosphorylated phosphatidylinositide 3-kinase (PI3K) increased both in 5-FU-tolerant subpopulations according to the 5-FU dose, and in gastric submucosal orthotopic xenografts of MKN45/5FU cells. Sequential administration of 5-FU and a PI3K inhibitor, GDC-0941, targeted the downstream ribosomal S6 kinase phosphorylation to significantly suppress 5-FU-tolerant subpopulations and tumor propagation of orthotopic MKN45/5FU xenografts. These results suggest that administration of 5-FU followed by GDC-0941 may suppress disease relapse after 5-FU-based gastric cancer chemotherapy.
Volume 7(1)
Pages 2262
Published 2017-5-23
DOI 10.1038/s41598-017-02548-9
PII 10.1038/s41598-017-02548-9
PMID 28536445
PMC PMC5442158
MeSH Animals Antimetabolites, Antineoplastic / pharmacology* Cell Line, Tumor Cell Proliferation / drug effects Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors Class I Phosphatidylinositol 3-Kinases / genetics Class I Phosphatidylinositol 3-Kinases / metabolism Codon Disease Models, Animal Dose-Response Relationship, Drug Drug Resistance, Neoplasm / drug effects* Drug Resistance, Neoplasm / genetics Fluorouracil / pharmacology* Genetic Variation Heterografts Humans Mice Neoplasms / genetics Neoplasms / metabolism Neoplasms / pathology Phenotype Phosphatidylinositol 3-Kinases / genetics Phosphatidylinositol 3-Kinases / metabolism Phosphoinositide-3 Kinase Inhibitors* Phosphorylation Proteome Proteomics / methods Ribosomal Protein S6 Kinases, 90-kDa / metabolism Signal Transduction
IF 3.998
Human and Animal Cells MKN45(RCB1001) MKN74(RCB1002)