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 |
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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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