Function of Integrin-Linked Kinase in Modulating the Stemness of IL-6–Abundant Breast Cancer Cells by Regulating γ-Secretase–Mediated Notch1 Activation in Caveolae12
| العنوان: | Function of Integrin-Linked Kinase in Modulating the Stemness of IL-6–Abundant Breast Cancer Cells by Regulating γ-Secretase–Mediated Notch1 Activation in Caveolae12 |
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| المؤلفون: | Hsu, En-Chi, Kulp, Samuel K., Huang, Han-Li, Tu, Huang-Ju, Salunke, Santosh B., Sullivan, Nicholas J., Sun, Duxin, Wicha, Max S., Shapiro, Charles L., Chen, Ching-Shih |
| المصدر: | Neoplasia (New York, N.Y.) |
| بيانات النشر: | Neoplasia Press, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | DAPT, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, Blotting, Western, NCT, nicastrin, Fluorescent Antibody Technique, Breast Neoplasms, Mice, SCID, Protein Serine-Threonine Kinases, Caveolae, Real-Time Polymerase Chain Reaction, Article, Gene Expression Regulation, Enzymologic, Immunoenzyme Techniques, Mice, Membrane Microdomains, GSK3β, glycogen synthase kinase 3β, Mice, Inbred NOD, Tumor Cells, Cultured, Animals, Humans, Immunoprecipitation, RNA, Messenger, NICD, Notch intracellular domain, RNA, Small Interfering, IL-6, interleukin-6, TNBC, triple negative breast cancer, PEN-2, presenilin enhancer 2, Receptors, Notch, Interleukin-6, Reverse Transcriptase Polymerase Chain Reaction, CSC, cancer stem cell, ILK, integrin-linked kinase, Gene Expression Regulation, Neoplastic, PS1, presenilin-1, embryonic structures, OCTG, n-octyl d-glucopyranoside, Neoplastic Stem Cells, Female, DAPI, 4',6-diamidino-2-phenylindole, Amyloid Precursor Protein Secretases, PI3K, phosphoinositide 3-kinase, Signal Transduction |
| الوصف: | Interleukin-6 (IL-6) and Notch signaling are important regulators of breast cancer stem cells (CSCs), which drive the malignant phenotype through self-renewal, differentiation, and development of therapeutic resistance. We investigated the role of integrin-linked kinase (ILK) in regulating IL-6-driven Notch1 activation and the ability to target breast CSCs through ILK inhibition. Ectopic expression/short hairpin RNA-mediated knockdown of ILK, pharmacological inhibition of ILK with the small molecule T315, Western blot analysis, immunofluorescence, and luciferase reporter assays were used to evaluate the regulation of IL-6-driven Notch1 activation by ILK in IL-6-producing triple-negative breast cancer cell lines (MDA-MB-231, SUM-159) and in MCF-7 and MCF-7(IL-6) cells. The effects of ILK on γ-secretase complex assembly and cellular localization were determined by immunofluorescence, Western blots of membrane fractions, and immunoprecipitation. In vivo effects of T315-induced ILK inhibition on CSCs in SUM-159 xenograft models were assessed by mammosphere assays, flow cytometry, and tumorigenicity assays. Results show that the genetic knockdown or pharmacological inhibition of ILK suppressed Notch1 activation and the abundance of the γ-secretase components presenilin-1, nicastrin, and presenilin enhancer 2 at the posttranscriptional level via inhibition of caveolin-1-dependent membrane assembly of the γ-secretase complex. Accordingly, knockdown of ILK inhibited breast CSC-like properties in vitro and the breast CSC subpopulation in vivo in xenograft tumor models. Based on these findings, we propose a novel function of ILK in regulating γ-secretase-mediated Notch1 activation, which suggests the targeting of ILK as a therapeutic approach to suppress IL-6-induced breast CSCs. |
| اللغة: | English |
| تدمد: | 1476-5586 1522-8002 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=pmid________::438a8df04965f10f62abbb6ef37caaef http://europepmc.org/articles/PMC4719004 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.pmid..........438a8df04965f10f62abbb6ef37caaef |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765586 15228002 |
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