title: Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine &Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Rong
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Yuan
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Qu
authors.affiliation: Department of Laboratory Medicine &Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Guan
authors.affiliation: Department of Laboratory Medicine &Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.affiliation: Hubei Key Laboratory of Tumor Biological Behaviors &Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Leng
authors.affiliation: Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Lang
authors.initials: L
authors.lastname: Bu
authors.affiliation: Animal experiment center of wuhan university/Animal Biosafety Level-III laboratory, No. 115 Donghu Road, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Laboratory Medicine &Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Fu-Bing
authors.initials: FB
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000070416:Antagomirs / Q000494:pharmacology; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology*; D009363:Neoplasm Proteins / Q000502:physiology; D012334:RNA, Neoplasm / Q000037:antagonists & inhibitors / Q000235:genetics; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000502:physiology; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000502:physiology
chemical_list: D000070416:Antagomirs; C547183:MIRN10 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D015232:Dinoprostone