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The PI3K/Akt/GSK-3β/ROS/eIF2B pathway promotes breast cancer growth and metastasis via suppression of NK cell cytotoxicity and tumor cell susceptibility

OBJECTIVE: To examine the effect of pSer9-GSK-3β on breast cancer and to determine whether the underlying metabolic and immunological mechanism is associated with ROS/eIF2B and natural killer (NK) cells. METHODS: We employed TWS119 to inactivate GSK-3β by phosphorylating Ser9 and explored its effect...

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Autores principales: Jin, Fengjiao, Wu, Zhaozhen, Hu, Xiao, Zhang, Jiahui, Gao, Zihe, Han, Xiao, Qin, Junfang, Li, Chen, Wang, Yue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Chinese Anti-Cancer Association 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528454/
https://www.ncbi.nlm.nih.gov/pubmed/31119045
http://dx.doi.org/10.20892/j.issn.2095-3941.2018.0253
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author Jin, Fengjiao
Wu, Zhaozhen
Hu, Xiao
Zhang, Jiahui
Gao, Zihe
Han, Xiao
Qin, Junfang
Li, Chen
Wang, Yue
author_facet Jin, Fengjiao
Wu, Zhaozhen
Hu, Xiao
Zhang, Jiahui
Gao, Zihe
Han, Xiao
Qin, Junfang
Li, Chen
Wang, Yue
author_sort Jin, Fengjiao
collection PubMed
description OBJECTIVE: To examine the effect of pSer9-GSK-3β on breast cancer and to determine whether the underlying metabolic and immunological mechanism is associated with ROS/eIF2B and natural killer (NK) cells. METHODS: We employed TWS119 to inactivate GSK-3β by phosphorylating Ser9 and explored its effect on breast cancer and NK cells. The expression of GSK-3β, natural killer group 2 member D (NKG2D) ligands, eIF2B was quantified by PCR and Western blot. We measured intracellular reactive oxygen species (ROS) and mitochondrial ROS using DCFH-DA and MitoSOX(TM) probe, respectively, and conducted quantitative analysis of cellular respiration on 4T1 cells with mitochondrial respiratory chain complex I/III kits. RESULTS: Our investigation revealed that TWS119 downregulated NKG2D ligands (H60a and Rae1), suppressed the cytotoxicity of NK cells, and promoted the migration of 4T1 murine breast cancer cells. Nevertheless, LY290042, which attenuates p-GSK-3β formation by inhibiting the PI3K/Akt pathway, reversed these effects. We also found that higher expression of pSer9-GSK-3β induced higher levels of ROS, and observed that abnormality of mitochondrial respiratory chain complex I/III function induced the dysfunction of GSK-3β-induced electron transport chain, naturally disturbing the ROS level. In addition, the expression of NOX3 and NOX4 was significantly up-regulated, which affected the generation of ROS and associated with the metastasis of breast cancer. Furthermore, we found that the expression of pSer535-eIF2B promoted the expression of NKG2D ligands (Mult-1 and Rae1) following by expression of pSer9-GSK-3β and generation of ROS. CONCLUSIONS: The PI3K/Akt/GSK-3β/ROS/eIF2B pathway could regulate NK cell activity and sensitivity of tumor cells to NK cells, which resulted in breast cancer growth and lung metastasis. Thus, GSK-3β is a promising target of anti-tumor therapy.
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spelling pubmed-65284542019-05-22 The PI3K/Akt/GSK-3β/ROS/eIF2B pathway promotes breast cancer growth and metastasis via suppression of NK cell cytotoxicity and tumor cell susceptibility Jin, Fengjiao Wu, Zhaozhen Hu, Xiao Zhang, Jiahui Gao, Zihe Han, Xiao Qin, Junfang Li, Chen Wang, Yue Cancer Biol Med Original Article OBJECTIVE: To examine the effect of pSer9-GSK-3β on breast cancer and to determine whether the underlying metabolic and immunological mechanism is associated with ROS/eIF2B and natural killer (NK) cells. METHODS: We employed TWS119 to inactivate GSK-3β by phosphorylating Ser9 and explored its effect on breast cancer and NK cells. The expression of GSK-3β, natural killer group 2 member D (NKG2D) ligands, eIF2B was quantified by PCR and Western blot. We measured intracellular reactive oxygen species (ROS) and mitochondrial ROS using DCFH-DA and MitoSOX(TM) probe, respectively, and conducted quantitative analysis of cellular respiration on 4T1 cells with mitochondrial respiratory chain complex I/III kits. RESULTS: Our investigation revealed that TWS119 downregulated NKG2D ligands (H60a and Rae1), suppressed the cytotoxicity of NK cells, and promoted the migration of 4T1 murine breast cancer cells. Nevertheless, LY290042, which attenuates p-GSK-3β formation by inhibiting the PI3K/Akt pathway, reversed these effects. We also found that higher expression of pSer9-GSK-3β induced higher levels of ROS, and observed that abnormality of mitochondrial respiratory chain complex I/III function induced the dysfunction of GSK-3β-induced electron transport chain, naturally disturbing the ROS level. In addition, the expression of NOX3 and NOX4 was significantly up-regulated, which affected the generation of ROS and associated with the metastasis of breast cancer. Furthermore, we found that the expression of pSer535-eIF2B promoted the expression of NKG2D ligands (Mult-1 and Rae1) following by expression of pSer9-GSK-3β and generation of ROS. CONCLUSIONS: The PI3K/Akt/GSK-3β/ROS/eIF2B pathway could regulate NK cell activity and sensitivity of tumor cells to NK cells, which resulted in breast cancer growth and lung metastasis. Thus, GSK-3β is a promising target of anti-tumor therapy. Chinese Anti-Cancer Association 2019-02 /pmc/articles/PMC6528454/ /pubmed/31119045 http://dx.doi.org/10.20892/j.issn.2095-3941.2018.0253 Text en Copyright 2019 Cancer Biology & Medicine http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Original Article
Jin, Fengjiao
Wu, Zhaozhen
Hu, Xiao
Zhang, Jiahui
Gao, Zihe
Han, Xiao
Qin, Junfang
Li, Chen
Wang, Yue
The PI3K/Akt/GSK-3β/ROS/eIF2B pathway promotes breast cancer growth and metastasis via suppression of NK cell cytotoxicity and tumor cell susceptibility
title The PI3K/Akt/GSK-3β/ROS/eIF2B pathway promotes breast cancer growth and metastasis via suppression of NK cell cytotoxicity and tumor cell susceptibility
title_full The PI3K/Akt/GSK-3β/ROS/eIF2B pathway promotes breast cancer growth and metastasis via suppression of NK cell cytotoxicity and tumor cell susceptibility
title_fullStr The PI3K/Akt/GSK-3β/ROS/eIF2B pathway promotes breast cancer growth and metastasis via suppression of NK cell cytotoxicity and tumor cell susceptibility
title_full_unstemmed The PI3K/Akt/GSK-3β/ROS/eIF2B pathway promotes breast cancer growth and metastasis via suppression of NK cell cytotoxicity and tumor cell susceptibility
title_short The PI3K/Akt/GSK-3β/ROS/eIF2B pathway promotes breast cancer growth and metastasis via suppression of NK cell cytotoxicity and tumor cell susceptibility
title_sort pi3k/akt/gsk-3β/ros/eif2b pathway promotes breast cancer growth and metastasis via suppression of nk cell cytotoxicity and tumor cell susceptibility
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528454/
https://www.ncbi.nlm.nih.gov/pubmed/31119045
http://dx.doi.org/10.20892/j.issn.2095-3941.2018.0253
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