title: Inhibition of breast cancer resistance protein (ABCG2) in human myeloid dendritic cells induces potent tolerogenic functions during LPS stimulation.
abstract: Breast cancer resistance protein (ABCG2), a member of the ATP-binding cassette transporters has been identified as a major determinant of multidrug resistance (MDR) in cancer cells, but ABC transporter inhibition has limited therapeutic value in vivo. In this research, we demonstrated that inhibition of efflux transporters ABCG2 induced the generation of tolerogenic DCs from human peripheral blood myeloid DCs (mDCs). ABCG2 expression was present in mDCs and was further increased by LPS stimulation. Treatment of CD1c+ mDCs with an ABCG2 inhibitor, Ko143, during LPS stimulation caused increased production of IL-10 and decreased production of pro-inflammatory cytokines and decreased expression of CD83 and CD86. Moreover, inhibition of ABCG2 in monocyte-derived DCs (MDDCs) abrogated the up-regulation of co-stimulatory molecules and production of pro-inflammatory cytokines in these cells in response to LPS. Furthermore, CD1c+ mDCs stimulated with LPS plus Ko143 inhibited the proliferation of allogeneic and superantigen-specific syngenic CD4+ T cells and promoted expansion of CD25+FOXP3+ regulatory T (Treg) cells in an IL-10-dependent fashion. These tolerogenic effects of ABCG2 inhibition could be abolished by ERK inhibition. Thus, we demonstrated that inhibition of ABCG2 in LPS-stimulated mDCs can potently induce tolerogenic potentials in these cells, providing crucial new information that could lead to development of better strategies to combat MDR cancer.
authors.affiliation: Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Jun-O
authors.initials: JO
authors.lastname: Jin
authors.affiliation: Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Ka-Wing
authors.initials: KW
authors.lastname: Wong
authors.affiliation: Department of Chemistry, Pukyong National University, Busan, South Korea.
authors.forename: Minseok
authors.initials: M
authors.lastname: Kwak
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Ian R
authors.initials: IR
authors.lastname: van Driel
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D054659:Diketopiperazines; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D022423:Myeloid Cells / Q000166:cytology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D008070:Lipopolysaccharides; D009363:Neoplasm Proteins; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases; D000241:Adenosine
references.citation: Blood. 2006 Aug 1;108(3):804-11
references.pmid: 16861339
references.citation: J Exp Med. 1998 Dec 7;188(11):2175-80
references.pmid: 9841930
references.citation: J Biol Chem. 2006 Aug 18;281(33):23812-23
references.pmid: 16785230
references.citation: Clin Cancer Res. 2007 Jun 1;13(11):3276-85
references.pmid: 17545533
references.citation: Nat Rev Immunol. 2007 Jan;7(1):19-30
references.pmid: 17170756
references.citation: Cancer Immunol Immunother. 2007 Jan;56(1):48-59
references.pmid: 16612596
references.citation: Eur J Immunol. 2014 Jan;44(1):80-92
references.pmid: 24114554
references.citation: Curr Mol Pharmacol. 2008 Jun;1(2):93-105
references.pmid: 19079736
references.citation: Blood. 2006 Oct 1;108(7):2307-15
references.pmid: 16778140
references.citation: Annu Rev Immunol. 2003;21:685-711
references.pmid: 12615891
references.citation: Cell. 2000 Nov 22;103(5):757-68
references.pmid: 11114332
references.citation: Nat Rev Drug Discov. 2006 Mar;5(3):219-34
references.pmid: 16518375
references.citation: Cancer Metastasis Rev. 2006 Sep;25(3):323-31
references.pmid: 16983515
references.citation: Cochrane Database Syst Rev. 2012 Jan 18;1:CD004386
references.pmid: 22258955
references.citation: Hum Immunol. 2001 Oct;62(10):1073-80
references.pmid: 11600213
references.citation: Front Immunol. 2012 May 18;3:123
references.pmid: 22629255
references.citation: Adv Immunol. 2010;108:111-65
references.pmid: 21056730
references.citation: Cancer Res. 1999 Jan 15;59(2):455-61
references.pmid: 9927062
references.citation: Blood. 2006 Sep 1;108(5):1435-40
references.pmid: 16684955
references.citation: Cancer. 2001 Sep 15;92(6):1577-90
references.pmid: 11745237
references.citation: Immunol Cell Biol. 2012 Feb;90(2):206-15
references.pmid: 21445088
references.citation: Nat Rev Cancer. 2002 Jan;2(1):48-58
references.pmid: 11902585
references.citation: J Exp Med. 2011 Feb 14;208(2):235-49
references.pmid: 21300911
references.citation: Blood. 2010 Nov 18;116(20):4077-85
references.pmid: 20716770
references.citation: Immunity. 2013 Jul 25;39(1):38-48
references.pmid: 23890062
references.citation: Autoimmun Rev. 2010 Nov;10(1):8-17
references.pmid: 20678591
references.citation: J Immunol. 2001 Mar 15;166(6):3837-45
references.pmid: 11238627
references.citation: Cancer Cell. 2009 Mar 3;15(3):195-206
references.pmid: 19249678
references.citation: J Immunol. 2006 May 1;176(9):5191-8
references.pmid: 16621983
references.citation: Trends Immunol. 2002 Sep;23(9):445-9
references.pmid: 12200066
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6924-9
references.pmid: 9618515
references.citation: Immunity. 1998 Sep;9(3):315-23
references.pmid: 9768751
references.citation: Cochrane Database Syst Rev. 2012 Sep 12;(9):CD006247
references.pmid: 22972091
references.citation: Exp Eye Res. 2007 Apr;84(4):626-34
references.pmid: 17254566
references.citation: Curr Opin Immunol. 2007 Apr;19(2):217-23
references.pmid: 17306521
references.citation: Clin Immunol. 2012 Mar;142(3):332-42
references.pmid: 22225835
references.citation: Blood. 2008 Sep 15;112(6):2353-9
references.pmid: 18625884
references.citation: J Clin Oncol. 2007 Feb 1;25(4):411-7
references.pmid: 17179098
references.citation: Oncogene. 2003 Oct 20;22(47):7468-85
references.pmid: 14576852
references.citation: Cancer Immunol Immunother. 2011 Apr;60(4):457-66
references.pmid: 21258790
references.citation: Annu Rev Cell Dev Biol. 2007;23:675-99
references.pmid: 17645413
references.citation: Nat Rev Cancer. 2010 Feb;10(2):147-56
references.pmid: 20075923
references.citation: Cancer Lett. 2013 Oct 1;339(1):107-15
references.pmid: 23879965
references.citation: Trends Immunol. 2009 Sep;30(9):421-9
references.pmid: 19699682
references.citation: J Immunol. 2002 Feb 15;168(4):1572-8
references.pmid: 11823484