title: IL6 induces TAM resistance via kinase-specific phosphorylation of ERα in OVCA cells.
abstract: About 40-60% of ovarian cancer (OVCA) cases express ERα, but only a small proportion of patients respond clinically to anti-estrogen treatment with estrogen receptor (ER) antagonist tamoxifen (TAM). The mechanism of TAM resistance in the course of OVCA progression remains unclear. However, IL6 plays a critical role in the development and progression of OVCA. Our recent results indicated that IL6 secreted by OVCA cells may promote the resistance of these cells to TAM via ER isoforms and steroid hormone receptor coactivator-1. Here we demonstrate that both exogenous (a relatively short period of treatment with recombinant IL6) and endogenous IL6 (generated as a result of transfection with a plasmid encoding sense IL6) increases expression of pERα-Ser118 and pERα-Ser167 in non-IL6-expressing A2780 cells, while deleting endogenous IL6 expression in IL6-overexpressing CAOV-3 cells (by transfection with a plasmid encoding antisense IL6) reduces expression of pERα-Ser118 and pERα-Ser167, indicating that IL6-induced TAM resistance may also be associated with increased expression of pERα-Ser118 and pERα-Ser167 in OVCA cells. Results of further investigation indicate that IL6 phosphorylates ERα at Ser118 and Ser167 by triggering activation of MEK/ERK and phosphotidylinositol 3 kinase/Akt signaling, respectively, to activate the ER pathway and thereby induce OVCA cells resistance to TAM. These results indicate that IL6 secreted by OVCA cells may also contribute to the refractoriness of these cells to TAM via the crosstalk between ER and IL6-mediated intracellular signal transduction cascades. Overexpression of IL6 not only plays an important role in OVCA progression but also promotes TAM resistance. Our results indicate that TAM-IL6-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 HazardTianjin, People's Republic of ChinaDepartment of Pathogenic Biology and ImmunologyLogistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, Number 1, Tianjin 300309, People's Republic of ChinaDepartment of Infectious DiseasesAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of PharmacologyLogistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of Gynecology and ObstetricsAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China Tianjin Key Laboratory for Prevention and Control of Occupational and Environmental HazardTianjin, People's Republic of ChinaDepartment of Pathogenic Biology and ImmunologyLogistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, Number 1, Tianjin 300309, People's Republic of ChinaDepartment of Infectious DiseasesAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of PharmacologyLogistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of Gynecology and ObstetricsAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China wangyue6808@126.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory for Prevention and Control of Occupational and Environmental HazardTianjin, People's Republic of ChinaDepartment of Pathogenic Biology and ImmunologyLogistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, Number 1, Tianjin 300309, People's Republic of ChinaDepartment of Infectious DiseasesAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of PharmacologyLogistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of Gynecology and ObstetricsAffiliated 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: Tianjin Key Laboratory for Prevention and Control of Occupational and Environmental HazardTianjin, People's Republic of ChinaDepartment of Pathogenic Biology and ImmunologyLogistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, Number 1, Tianjin 300309, People's Republic of ChinaDepartment of Infectious DiseasesAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of PharmacologyLogistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of Gynecology and ObstetricsAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China.
authors.forename: Xiao Qin
authors.initials: XQ
authors.lastname: Guo
authors.affiliation: Tianjin Key Laboratory for Prevention and Control of Occupational and Environmental HazardTianjin, People's Republic of ChinaDepartment of Pathogenic Biology and ImmunologyLogistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, Number 1, Tianjin 300309, People's Republic of ChinaDepartment of Infectious DiseasesAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of PharmacologyLogistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of Gynecology and ObstetricsAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Tianjin Key Laboratory for Prevention and Control of Occupational and Environmental HazardTianjin, People's Republic of ChinaDepartment of Pathogenic Biology and ImmunologyLogistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, Number 1, Tianjin 300309, People's Republic of ChinaDepartment of Infectious DiseasesAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of PharmacologyLogistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of Gynecology and ObstetricsAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Tianjin Key Laboratory for Prevention and Control of Occupational and Environmental HazardTianjin, People's Republic of ChinaDepartment of Pathogenic Biology and ImmunologyLogistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, Number 1, Tianjin 300309, People's Republic of ChinaDepartment of Infectious DiseasesAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of PharmacologyLogistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of Gynecology and ObstetricsAffiliated Hospital of 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: Tianjin Key Laboratory for Prevention and Control of Occupational and Environmental HazardTianjin, People's Republic of ChinaDepartment of Pathogenic Biology and ImmunologyLogistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, Number 1, Tianjin 300309, People's Republic of ChinaDepartment of Infectious DiseasesAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of PharmacologyLogistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of Gynecology and ObstetricsAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China.
authors.forename: Cun
authors.initials: C
authors.lastname: Xiu Hu
authors.affiliation: Tianjin Key Laboratory for Prevention and Control of Occupational and Environmental HazardTianjin, People's Republic of ChinaDepartment of Pathogenic Biology and ImmunologyLogistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, Number 1, Tianjin 300309, People's Republic of ChinaDepartment of Infectious DiseasesAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of PharmacologyLogistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of Gynecology and ObstetricsAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China.
authors.forename: Li Qun
authors.initials: LQ
authors.lastname: Mao
authors.affiliation: Tianjin Key Laboratory for Prevention and Control of Occupational and Environmental HazardTianjin, People's Republic of ChinaDepartment of Pathogenic Biology and ImmunologyLogistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, Number 1, Tianjin 300309, People's Republic of ChinaDepartment of Infectious DiseasesAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of PharmacologyLogistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of ChinaDepartment of Gynecology and ObstetricsAffiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D020935:MAP Kinase Signaling System; D010051:Ovarian Neoplasms; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D015850:Interleukin-6; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D013629:Tamoxifen; C506487:ESR1 protein, human; C508600:IL6 protein, human
keywords: Akt; ERK; interleukin-6 (IL-6); kinase-specific phosphorylation of Estrogen receptor (ER)α; ovarian cancer (OVCA); tamoxifen(TAM) resistance