Hexokinases II‐mediated glycolysis governs susceptibility to crizotinib in ALK‐positive non‐small cell lung cancer

Abstract Background Activation of ALK leads to a high level of aerobic glycolysis related to crizotinib insensitivity in anaplastic lymphoma kinase‐positive non‐small cell lung cancer (ALK+ NSCLC). The strategy and mechanism of glycolysis inhibition in sensitizing ALK+ NSCLC cells to crizotinib requ...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Caiyu Lin, Hengyi Chen, Rui Han, Li Li, Conghua Lu, Shuai Hao, Yubo Wang, Yong He
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	2DG aerobic glycolysis anaplastic lymphoma kinase crizotinib tolerance hexokinases II Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/4bb9d66354ef4b3b930a41e96b102ed7
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:4bb9d66354ef4b3b930a41e96b102ed7
record_format	dspace
spelling	oai:doaj.org-article:4bb9d66354ef4b3b930a41e96b102ed72021-12-02T02:34:55ZHexokinases II‐mediated glycolysis governs susceptibility to crizotinib in ALK‐positive non‐small cell lung cancer1759-77141759-770610.1111/1759-7714.14184https://doaj.org/article/4bb9d66354ef4b3b930a41e96b102ed72021-12-01T00:00:00Zhttps://doi.org/10.1111/1759-7714.14184https://doaj.org/toc/1759-7706https://doaj.org/toc/1759-7714Abstract Background Activation of ALK leads to a high level of aerobic glycolysis related to crizotinib insensitivity in anaplastic lymphoma kinase‐positive non‐small cell lung cancer (ALK+ NSCLC). The strategy and mechanism of glycolysis inhibition in sensitizing ALK+ NSCLC cells to crizotinib requires further investigation. Methods The levels of glycolysis in H3122 and H2228 cells were evaluated through detection of glucose consumption and lactate production. MTT assay was used to explore the effects of glycolytic inhibitors on crizotinib sensitivity, and the potential mechanism of action were detected by colony formation, Ki67 incorporation assay, transwell assay, small interfering RNA technology and western blot analysis. Results ALK+ NSCLC cells exhibited significantly higher levels of glycolysis compared to ALK− NSCLC cells. Long‐term exposure to crizotinib could decrease the sensitivity of ALK+ NSCLC cells to crizotinib via increasing the levels of glycolysis related to hexokinases II (HK2). Crizotinib in combination with glycolysis inhibitor 2‐deoxy‐D‐glucose (2DG) synergistically inhibited proliferation, glycolysis, colony formation and invasion ability of ALK+ NSCLC cells. 2DG sensitization crizotinib might be associated with the inhibition of HK2‐mediated glycolysis and P‐ALK/AKT/mTOR signaling pathway in H3122 and H2228 cells. Conclusions These results indicate that HK2‐mediated glycolysis plays a crucial role in the increased tolerance of ALK+ NSCLC cells to crizotinib. 2DG may sensitize ALK+ NSCLC to crizotinib via suppression of HK2‐mediated glycolysis and the AKT/mTOR signaling pathway.Caiyu LinHengyi ChenRui HanLi LiConghua LuShuai HaoYubo WangYong HeWileyarticle2DGaerobic glycolysisanaplastic lymphoma kinasecrizotinib tolerancehexokinases IINeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENThoracic Cancer, Vol 12, Iss 23, Pp 3184-3193 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	2DG aerobic glycolysis anaplastic lymphoma kinase crizotinib tolerance hexokinases II Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	2DG aerobic glycolysis anaplastic lymphoma kinase crizotinib tolerance hexokinases II Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Caiyu Lin Hengyi Chen Rui Han Li Li Conghua Lu Shuai Hao Yubo Wang Yong He Hexokinases II‐mediated glycolysis governs susceptibility to crizotinib in ALK‐positive non‐small cell lung cancer
description	Abstract Background Activation of ALK leads to a high level of aerobic glycolysis related to crizotinib insensitivity in anaplastic lymphoma kinase‐positive non‐small cell lung cancer (ALK+ NSCLC). The strategy and mechanism of glycolysis inhibition in sensitizing ALK+ NSCLC cells to crizotinib requires further investigation. Methods The levels of glycolysis in H3122 and H2228 cells were evaluated through detection of glucose consumption and lactate production. MTT assay was used to explore the effects of glycolytic inhibitors on crizotinib sensitivity, and the potential mechanism of action were detected by colony formation, Ki67 incorporation assay, transwell assay, small interfering RNA technology and western blot analysis. Results ALK+ NSCLC cells exhibited significantly higher levels of glycolysis compared to ALK− NSCLC cells. Long‐term exposure to crizotinib could decrease the sensitivity of ALK+ NSCLC cells to crizotinib via increasing the levels of glycolysis related to hexokinases II (HK2). Crizotinib in combination with glycolysis inhibitor 2‐deoxy‐D‐glucose (2DG) synergistically inhibited proliferation, glycolysis, colony formation and invasion ability of ALK+ NSCLC cells. 2DG sensitization crizotinib might be associated with the inhibition of HK2‐mediated glycolysis and P‐ALK/AKT/mTOR signaling pathway in H3122 and H2228 cells. Conclusions These results indicate that HK2‐mediated glycolysis plays a crucial role in the increased tolerance of ALK+ NSCLC cells to crizotinib. 2DG may sensitize ALK+ NSCLC to crizotinib via suppression of HK2‐mediated glycolysis and the AKT/mTOR signaling pathway.
format	article
author	Caiyu Lin Hengyi Chen Rui Han Li Li Conghua Lu Shuai Hao Yubo Wang Yong He
author_facet	Caiyu Lin Hengyi Chen Rui Han Li Li Conghua Lu Shuai Hao Yubo Wang Yong He
author_sort	Caiyu Lin
title	Hexokinases II‐mediated glycolysis governs susceptibility to crizotinib in ALK‐positive non‐small cell lung cancer
title_short	Hexokinases II‐mediated glycolysis governs susceptibility to crizotinib in ALK‐positive non‐small cell lung cancer
title_full	Hexokinases II‐mediated glycolysis governs susceptibility to crizotinib in ALK‐positive non‐small cell lung cancer
title_fullStr	Hexokinases II‐mediated glycolysis governs susceptibility to crizotinib in ALK‐positive non‐small cell lung cancer
title_full_unstemmed	Hexokinases II‐mediated glycolysis governs susceptibility to crizotinib in ALK‐positive non‐small cell lung cancer
title_sort	hexokinases ii‐mediated glycolysis governs susceptibility to crizotinib in alk‐positive non‐small cell lung cancer
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/4bb9d66354ef4b3b930a41e96b102ed7
work_keys_str_mv	AT caiyulin hexokinasesiimediatedglycolysisgovernssusceptibilitytocrizotinibinalkpositivenonsmallcelllungcancer AT hengyichen hexokinasesiimediatedglycolysisgovernssusceptibilitytocrizotinibinalkpositivenonsmallcelllungcancer AT ruihan hexokinasesiimediatedglycolysisgovernssusceptibilitytocrizotinibinalkpositivenonsmallcelllungcancer AT lili hexokinasesiimediatedglycolysisgovernssusceptibilitytocrizotinibinalkpositivenonsmallcelllungcancer AT conghualu hexokinasesiimediatedglycolysisgovernssusceptibilitytocrizotinibinalkpositivenonsmallcelllungcancer AT shuaihao hexokinasesiimediatedglycolysisgovernssusceptibilitytocrizotinibinalkpositivenonsmallcelllungcancer AT yubowang hexokinasesiimediatedglycolysisgovernssusceptibilitytocrizotinibinalkpositivenonsmallcelllungcancer AT yonghe hexokinasesiimediatedglycolysisgovernssusceptibilitytocrizotinibinalkpositivenonsmallcelllungcancer
_version_	1718402348329467904

Hexokinases II‐mediated glycolysis governs susceptibility to crizotinib in ALK‐positive non‐small cell lung cancer

Ejemplares similares