Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil

Autor: Takashi Kobunai, Kohei Kume, Takeshi Iwaya, Mamoru Nukatsuka, Akari Konta, Kaoru Ishida, Kei Sato, Teiji Takechi, Chie Ito, Yukimi Ohmori, Yuka Koizumi, Satoshi Nishizuka
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Proteomics
0301 basic medicine
Proteome
medicine.medical_treatment
Ribosomal s6 kinase
Mice
Phosphatidylinositol 3-Kinases
0302 clinical medicine
Neoplasms
Phosphorylation
Phosphoinositide-3 Kinase Inhibitors
Multidisciplinary
biology
Stomach
Phenotype
medicine.anatomical_structure
Fluorouracil
030220 oncology & carcinogenesis
Heterografts
Medicine
Signal transduction
Signal Transduction
medicine.drug
Antimetabolites
Antineoplastic
Class I Phosphatidylinositol 3-Kinases
Science
Ribosomal Protein S6 Kinases
90-kDa
Article
03 medical and health sciences
Cell Line
Tumor
medicine
Animals
Humans
Codon
PI3K/AKT/mTOR pathway
Cell Proliferation
Chemotherapy
Dose-Response Relationship
Drug
business.industry
Genetic Variation
digestive system diseases
Disease Models
Animal
030104 developmental biology
Drug Resistance
Neoplasm
Cell culture
Cancer cell
Immunology
Cancer research
biology.protein
business
Zdroj: Scientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
Scientific Reports
ISSN: 2045-2322
Popis: 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.
Databáze: OpenAIRE
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