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

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...

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Autores principales:	Kaoru Ishida, Chie Ito, Yukimi Ohmori, Kohei Kume, Kei A. Sato, Yuka Koizumi, Akari Konta, Takeshi Iwaya, Mamoru Nukatsuka, Takashi Kobunai, Teiji Takechi, Satoshi S. Nishizuka
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/30e51fd4b7c44c4ca3d2cc55585da6d6
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spelling	oai:doaj.org-article:30e51fd4b7c44c4ca3d2cc55585da6d62021-12-02T15:06:11ZInhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil10.1038/s41598-017-02548-92045-2322https://doaj.org/article/30e51fd4b7c44c4ca3d2cc55585da6d62017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02548-9https://doaj.org/toc/2045-2322Abstract 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.Kaoru IshidaChie ItoYukimi OhmoriKohei KumeKei A. SatoYuka KoizumiAkari KontaTakeshi IwayaMamoru NukatsukaTakashi KobunaiTeiji TakechiSatoshi S. NishizukaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kaoru Ishida Chie Ito Yukimi Ohmori Kohei Kume Kei A. Sato Yuka Koizumi Akari Konta Takeshi Iwaya Mamoru Nukatsuka Takashi Kobunai Teiji Takechi Satoshi S. Nishizuka Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil
description	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.
format	article
author	Kaoru Ishida Chie Ito Yukimi Ohmori Kohei Kume Kei A. Sato Yuka Koizumi Akari Konta Takeshi Iwaya Mamoru Nukatsuka Takashi Kobunai Teiji Takechi Satoshi S. Nishizuka
author_facet	Kaoru Ishida Chie Ito Yukimi Ohmori Kohei Kume Kei A. Sato Yuka Koizumi Akari Konta Takeshi Iwaya Mamoru Nukatsuka Takashi Kobunai Teiji Takechi Satoshi S. Nishizuka
author_sort	Kaoru Ishida
title	Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil
title_short	Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil
title_full	Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil
title_fullStr	Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil
title_full_unstemmed	Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil
title_sort	inhibition of pi3k suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/30e51fd4b7c44c4ca3d2cc55585da6d6
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Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil

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