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Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down-regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells

Proteasome inhibition interfering with many cell signaling pathways has been extensively explored as a therapeutic strategy for cancers. Proteasome inhibitor YSY01A is a novel agent that has shown remarkable anti-tumor effects; however, its mechanisms of action are not fully understood. Here we repo...

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Autores principales: Huang, Wei, Yuan, Xia, Sun, Ting, Fan, Shujie, Wang, Jun, Zhou, Quan, Guo, Wei, Ran, Fuxiang, Ge, Zemei, Yang, Huayu, Li, Runtao, Cui, Jingrong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574410/
https://www.ncbi.nlm.nih.gov/pubmed/28883791
http://dx.doi.org/10.3389/fphar.2017.00476
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author Huang, Wei
Yuan, Xia
Sun, Ting
Fan, Shujie
Wang, Jun
Zhou, Quan
Guo, Wei
Ran, Fuxiang
Ge, Zemei
Yang, Huayu
Li, Runtao
Cui, Jingrong
author_facet Huang, Wei
Yuan, Xia
Sun, Ting
Fan, Shujie
Wang, Jun
Zhou, Quan
Guo, Wei
Ran, Fuxiang
Ge, Zemei
Yang, Huayu
Li, Runtao
Cui, Jingrong
author_sort Huang, Wei
collection PubMed
description Proteasome inhibition interfering with many cell signaling pathways has been extensively explored as a therapeutic strategy for cancers. Proteasome inhibitor YSY01A is a novel agent that has shown remarkable anti-tumor effects; however, its mechanisms of action are not fully understood. Here we report that YSY01A is capable of suppressing cancer cell survival by induction of apoptosis. Paradoxically, we find that YSY01A abrogates constitutive activation of STAT3 via proteasome-independent degradation of gp130 and JAK2, but not transcriptional regulation, in human A549 non-small cell lung cancer cells. The reduction in gp130 and JAK2 can be restored by co-treatment with 3-methyladenine, an early-stage autophagy lysosome and type I/III PI3K inhibitor. YSY01A also effectively inhibits cancer cell migration and lung xenograft tumor growth with little adverse effect on animals. Thus, our findings suggest that YSY01A represents a promising candidate for further development of novel anticancer therapeutics targeting the proteasome.
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spelling pubmed-55744102017-09-07 Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down-regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells Huang, Wei Yuan, Xia Sun, Ting Fan, Shujie Wang, Jun Zhou, Quan Guo, Wei Ran, Fuxiang Ge, Zemei Yang, Huayu Li, Runtao Cui, Jingrong Front Pharmacol Pharmacology Proteasome inhibition interfering with many cell signaling pathways has been extensively explored as a therapeutic strategy for cancers. Proteasome inhibitor YSY01A is a novel agent that has shown remarkable anti-tumor effects; however, its mechanisms of action are not fully understood. Here we report that YSY01A is capable of suppressing cancer cell survival by induction of apoptosis. Paradoxically, we find that YSY01A abrogates constitutive activation of STAT3 via proteasome-independent degradation of gp130 and JAK2, but not transcriptional regulation, in human A549 non-small cell lung cancer cells. The reduction in gp130 and JAK2 can be restored by co-treatment with 3-methyladenine, an early-stage autophagy lysosome and type I/III PI3K inhibitor. YSY01A also effectively inhibits cancer cell migration and lung xenograft tumor growth with little adverse effect on animals. Thus, our findings suggest that YSY01A represents a promising candidate for further development of novel anticancer therapeutics targeting the proteasome. Frontiers Media S.A. 2017-08-24 /pmc/articles/PMC5574410/ /pubmed/28883791 http://dx.doi.org/10.3389/fphar.2017.00476 Text en Copyright © 2017 Huang, Yuan, Sun, Fan, Wang, Zhou, Guo, Ran, Ge, Yang, Li and Cui. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Huang, Wei
Yuan, Xia
Sun, Ting
Fan, Shujie
Wang, Jun
Zhou, Quan
Guo, Wei
Ran, Fuxiang
Ge, Zemei
Yang, Huayu
Li, Runtao
Cui, Jingrong
Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down-regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells
title Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down-regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells
title_full Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down-regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells
title_fullStr Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down-regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells
title_full_unstemmed Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down-regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells
title_short Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down-regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells
title_sort proteasome inhibitor ysy01a abrogates constitutive stat3 signaling via down-regulation of gp130 and jak2 in human a549 lung cancer cells
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574410/
https://www.ncbi.nlm.nih.gov/pubmed/28883791
http://dx.doi.org/10.3389/fphar.2017.00476
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