title: Autocrine production of interleukin-6 confers ovarian cancer cells resistance to tamoxifen via ER isoforms and SRC-1.
abstract: Although 40-60% of ovarian cancer (OVCA)s express estrogen receptor (ER)α, only a minor proportion of patients respond to anti-estrogen treatment with ER antagonist tamoxifen (TAM). The mechanism underlying TAM resistance in the course of OVCA progression is incompletely understood. However, interleukin-6 (IL-6) plays a critical role in the development and progression of OVCA. Here we explore an association between IL-6 and TAM resistance. We demonstrate that both exogenous (a relatively short period of treatment with recombinant IL-6) and endogenous IL-6 (by transfecting with plasmid encoding for sense IL-6) induce TAM resistance in non-IL-6-expressing A2780 cells, while deleting of endogenous IL-6 expression in IL-6-overexpressing CAOV-3 cells (by transfecting with plasmid encoding for antisense IL-6) promotes the sensitivity of these cells to TAM. Further investigation indicates that TAM resistance caused by IL-6 is associated with the alteration of ERα, ERβ and steroid hormone receptor coactivator (SRC)-1 expression levels, the protein interactions between SRC-1 and ERα, but not ERβ, as well as blockage of estrogen-induced ER receptor nuclear translocation. These results show that IL-6 secreted by OVCA cells may contribute to the refractoriness of these cells to TAM via ER isoforms and SRC-1. Overexpression of IL-6 not only plays an important role in OVCA progression but also contributes to TAM resistance. Our studies suggest that TAM-IL-6-targeted adjunctive therapy may lead to a more effective intervention than TAM alone.
authors.affiliation: Tianjin Key Laboratory for Prevention and Control of Occupational and Environmental Hazard, Tianjin, People's Republic of China; Department of Immunology, Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China. Electronic address: wangyue6808@126.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Immunology, Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Immunology, Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China.
authors.forename: Xiao Lei
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of of Infectious Diseases, Affiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China.
authors.forename: Xiu Long
authors.initials: XL
authors.lastname: Niu
authors.affiliation: Department of of Gynaecology and Obstetrics, Affiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Immunology, Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China.
authors.forename: Zong Min
authors.initials: ZM
authors.lastname: Li
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics* / Q000378:metabolism; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D015850:Interleukin-6; D056920:Nuclear Receptor Coactivator 1; D034741:RNA, Small Interfering; D013629:Tamoxifen; D000093242:Interleukin-6 Inhibitors; C506487:ESR1 protein, human; C508600:IL6 protein, human; C538859:NCOA1 protein, human
keywords: Estrogen receptor (ER) isoforms; Interleukin-6 (IL-6); Ovarian cancer (OVCA); Steroid hormone receptor coactivator (SRC)-1; Tamoxifen (TAM) resistance