Integrin-linked kinase as a novel molecular switch of the IL-6-NF-κB signaling loop in breast cancer

Hsu E.-C.Kulp S.K.Huang H.-L.Tu H.-J.Chao M.-W.Tseng Y.-C.Yang M.-C.Salunke S.B.Sullivan N.J.Chen W.-C.Zhang J.Teng C.-M.WEN-MEI FUSun D.Wicha M.S.Shapiro C.L.Chen C.-S.2021-06-012021-06-0120151433334https://scholars.lib.ntu.edu.tw/handle/123456789/564578Substantial evidence has clearly demonstrated the role of the IL-6-NF-κB signaling loop in promoting aggressive phenotypes in breast cancer. However, the exact mechanism by which this inflammatory loop is regulated remains to be defined. Here, we report that integrin-linked kinase (ILK) acts as a molecular switch for this feedback loop. Specifically, we show that IL-6 induces ILK expression via E2F1 upregulation, which, in turn, activates NF-κB signaling to facilitate IL-6 production. shRNAmediated knockdown or pharmacological inhibition of ILK disrupted this IL-6-NF-κB signaling loop, and blocked IL-6-induced cancer stem cells in vitro and estrogen-independent tumor growth in vivo. Together, these findings establish ILK as an intermediary effector of the IL-6-NF-κB feedback loop and a promising therapeutic target for breast cancer. ? The Author 2016. Published by Oxford University Press. All rights reserved.[SDGs]SDG3cyclin D1; cyclin dependent kinase 2; doxycycline; immunoglobulin enhancer binding protein; integrin linked kinase; interleukin 6; lentivirus vector; messenger RNA; short hairpin RNA; STAT3 protein; transcription factor E2F1; immunoglobulin enhancer binding protein; integrin-linked kinase; interleukin 6; protein serine threonine kinase; animal experiment; animal model; animal tissue; Article; breast cancer; cancer gene therapy; cancer inhibition; cancer stem cell; cancer survival; cell proliferation; controlled study; cytokine production; cytokine release; ectopic expression; enzyme activation; enzyme active site; feedback system; female; gene overexpression; gene silencing; gene switching; human; human cell; human tissue; immunohistochemistry; MCF 7 cell line; molecular switch; mouse; nonhuman; nonviral gene therapy; priority journal; protein expression; protein phosphorylation; recurrence free survival; signal transduction; transactivation; upregulation; viral gene delivery system; breast tumor; metabolism; physiology; Breast Neoplasms; Humans; Interleukin-6; NF-kappa B; Protein-Serine-Threonine Kinases; Signal TransductionIntegrin-linked kinase as a novel molecular switch of the IL-6-NF-κB signaling loop in breast cancerjournal article10.1093/carcin/bgw020269055832-s2.0-84963623538