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En-Chi thesis-final2.pdf (28.75 MB)

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Targeting ILK to eliminate IL-6 induced cancer stem cell phenotype

Hsu, En-Chi
http://rave.ohiolink.edu/etdc/view?acc_num=osu1397560686

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Pharmacy.
Cancer stem cell (CSC) has been associated with the aggressive phenotype of cancer, including potent cancer initiation, drug resistance and metastasis. Triple negative breast cancer (TNBC), a breast cancer subtype with aggressive behavior and no effective targeting therapy, has been shown correlations with autocrine interleukin-6 (IL-6) dependent survival and increasing CSC population. The inflammatory cytokine IL-6 induces CSC by activating STAT3 and NF-kB pathway. Integrin-linked kinase (ILK), which links cell-adhesion receptors, integrins and growth factors to the actin cytoskeleton and regulates multiple signaling pathways such as Akt, AP-1 and NF-kB pathways, is highly expressed in various cancers. In breast cancer cell lines, we showed that ILK expression is tightly associated with IL-6 expression and Notch1 activation, which is important for maintaining the self-renewal capacity of CSC. The objective of this study is to characterize the regulatory interactions among IL-6, ILK, and Notch1 in breast CSC. Our work shows that IL-6 upregulated ILK expression via E2F1 which, in turn, amplified the IL-6-NF-kB positive signaling loop and stimulated downstream Notch1 activation. We also identified a novel role for ILK in the maturation of gamma-secretase, which cleaves and activates Notch 1. Immunohistochemical staining of a human breast tumor tissue microarray revealed a positive correlation between ILK and IL-6 expression. Moreover, high ILK expression showed low relapse-free survival probability (P = 0.045) among subgroup of patients with high IL-6 expression. These data indicate an integral role of ILK in IL-6-mediated signaling and consequent induction in CSC; thereby suggesting a novel strategy to target this cancer cell subpopulation through ILK inhibition. Indeed, the ILK inhibitor, T315, suppressed IL-6-induced Notch1 activation, breast CSC populations, and IL-6-driven breast xenograft tumor formation. In summary, our findings identified ILK as an inducible oncokinase that is responsive to the inflammatory cytokine, IL-6, and showed that ILK is a novel regulator of CSC. These results provide a rationale for targeting IL-6-induced tumorigenesis via inhibition of ILK.
Ching-Shih Chen (Advisor)
Robert Brueggemeier (Committee Member)
Charles Shapiro (Committee Member)
Roger Briesewitz (Committee Member)
Chenglong Li (Committee Member)
137 p.
Biochemistry; Biomedical Research; Molecular Biology; Pharmaceuticals

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Citations

  • Hsu, E.-C. (2014). Targeting ILK to eliminate IL-6 induced cancer stem cell phenotype [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397560686

    APA Style (7th edition)

  • Hsu, En-Chi. Targeting ILK to eliminate IL-6 induced cancer stem cell phenotype. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1397560686.

    MLA Style (8th edition)

  • Hsu, En-Chi. "Targeting ILK to eliminate IL-6 induced cancer stem cell phenotype." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397560686

    Chicago Manual of Style (17th edition)

osu1397560686
57
© 2014, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.