Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2

Chemotherapies often induce drug-resistance in cancer cells and simultaneously stimulate proliferation and activation of Myeloid-Derived Suppressor Cells (MDSCs) to inhibit anti-tumor T cells, thus result in poor prognosis of patients with breast cancers. To date, the mechanism underlying the expans...

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Main Authors:	Rong, Yuan, Yuan, Chun-Hui, Qu, Zhen, Zhou, Hu, Guan, Qing, Yang, Na, Leng, Xiao-Hua, Bu, Lang, Wu, Ke, Wang, Fu-Bing
Format:	Online
Language:	English
Published:	Nature Publishing Group 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817121/

id	pubmed-4817121
recordtype	oai_dc
spelling	pubmed-48171212016-04-05 Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2 Rong, Yuan Yuan, Chun-Hui Qu, Zhen Zhou, Hu Guan, Qing Yang, Na Leng, Xiao-Hua Bu, Lang Wu, Ke Wang, Fu-Bing Article Chemotherapies often induce drug-resistance in cancer cells and simultaneously stimulate proliferation and activation of Myeloid-Derived Suppressor Cells (MDSCs) to inhibit anti-tumor T cells, thus result in poor prognosis of patients with breast cancers. To date, the mechanism underlying the expansion of MDSCs in response to chemotherapies is poorly understood. In the present study, we used in vitro cell culture and in vivo animal studies to demonstrate that doxorubicin-resistant breast cancer cells secret significantly more prostaglandin E2 (PGE2) than their parental doxorubicin-sensitive cells. The secreted PGE2 can stimulate expansion and polymerization of MDSCs by directly target to its receptors, EP2/EP4, on the surface of MDSCs, which consequently triggers production of miR-10a through activating PKA signaling. More importantly, activated MDSCs can inhibit CD4+CD25− T cells as evidenced by reduced proliferation and IFN-γ release. In order to determine the molecular pathway that involves miR-10a mediated activation of MDSCs, biochemical and pharmacological studies were carried out. We found that miR-10a can activate AMPK signaling to promote expansion and activation of MDSCs. Thus, these results reveal, for the first time, a novel role of PGE2/miR-10a/AMPK signaling axis in chemotherapy-induced immune resistance, which might be targeted for treatment of chemotherapy resistant tumors. Nature Publishing Group 2016-04-01 /pmc/articles/PMC4817121/ /pubmed/27032536 http://dx.doi.org/10.1038/srep23824 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Rong, Yuan Yuan, Chun-Hui Qu, Zhen Zhou, Hu Guan, Qing Yang, Na Leng, Xiao-Hua Bu, Lang Wu, Ke Wang, Fu-Bing
spellingShingle	Rong, Yuan Yuan, Chun-Hui Qu, Zhen Zhou, Hu Guan, Qing Yang, Na Leng, Xiao-Hua Bu, Lang Wu, Ke Wang, Fu-Bing Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2
author_facet	Rong, Yuan Yuan, Chun-Hui Qu, Zhen Zhou, Hu Guan, Qing Yang, Na Leng, Xiao-Hua Bu, Lang Wu, Ke Wang, Fu-Bing
author_sort	Rong, Yuan
title	Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2
title_short	Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2
title_full	Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2
title_fullStr	Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2
title_full_unstemmed	Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2
title_sort	doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing pge2
description	Chemotherapies often induce drug-resistance in cancer cells and simultaneously stimulate proliferation and activation of Myeloid-Derived Suppressor Cells (MDSCs) to inhibit anti-tumor T cells, thus result in poor prognosis of patients with breast cancers. To date, the mechanism underlying the expansion of MDSCs in response to chemotherapies is poorly understood. In the present study, we used in vitro cell culture and in vivo animal studies to demonstrate that doxorubicin-resistant breast cancer cells secret significantly more prostaglandin E2 (PGE2) than their parental doxorubicin-sensitive cells. The secreted PGE2 can stimulate expansion and polymerization of MDSCs by directly target to its receptors, EP2/EP4, on the surface of MDSCs, which consequently triggers production of miR-10a through activating PKA signaling. More importantly, activated MDSCs can inhibit CD4+CD25− T cells as evidenced by reduced proliferation and IFN-γ release. In order to determine the molecular pathway that involves miR-10a mediated activation of MDSCs, biochemical and pharmacological studies were carried out. We found that miR-10a can activate AMPK signaling to promote expansion and activation of MDSCs. Thus, these results reveal, for the first time, a novel role of PGE2/miR-10a/AMPK signaling axis in chemotherapy-induced immune resistance, which might be targeted for treatment of chemotherapy resistant tumors.
publisher	Nature Publishing Group
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817121/
_version_	1613560863146377216

Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2

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