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

En Chi Hsu; Samuel K. Kulp; Han Li Huang; Huang Ju Tu; Min Wu Chao; Yu Chou Tseng; Ming Chen Yang; Santosh B. Salunke; Nicholas J. Sullivan; Wen Chung Chen; Jianying Zhang; Che Ming Teng; Wen Mei Fu; Duxin Sun; Max S. Wicha; Charles L. Shapiro; Ching Shih Chen

doi:10.1093/carcin/bgw020

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

En Chi Hsu, Samuel K. Kulp, Han Li Huang, Huang Ju Tu, Min Wu Chao, Yu Chou Tseng, Ming Chen Yang, Santosh B. Salunke, Nicholas J. Sullivan, Wen Chung Chen, Jianying Zhang, Che Ming Teng, Wen Mei Fu, Duxin Sun, Max S. Wicha, Charles L. Shapiro, Ching Shih Chen

Ph.D. Program in Drug Discovery and Development Industry

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

Abstract

Substantial 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.

Original language	English
Pages (from-to)	430-442
Number of pages	13
Journal	Carcinogenesis
Volume	37
Issue number	4
DOIs	https://doi.org/10.1093/carcin/bgw020
Publication status	Published - Oct 29 2015

ASJC Scopus subject areas

Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/carcin/bgw020

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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., Fu, W. M., Sun, D., Wicha, M. S., Shapiro, C. L., & Chen, C. S. (2015). Integrin-linked kinase as a novel molecular switch of the IL-6-NF-κB signaling loop in breast cancer. Carcinogenesis, 37(4), 430-442. https://doi.org/10.1093/carcin/bgw020

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abstract = "Substantial 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.",

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AU - Hsu, En Chi

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AU - Chao, Min Wu

AU - Tseng, Yu Chou

AU - Yang, Ming Chen

AU - Salunke, Santosh B.

AU - Sullivan, Nicholas J.

AU - Chen, Wen Chung

AU - Zhang, Jianying

AU - Teng, Che Ming

AU - Fu, Wen Mei

AU - Sun, Duxin

AU - Wicha, Max S.

AU - Shapiro, Charles L.

AU - Chen, Ching Shih

PY - 2015/10/29

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N2 - Substantial 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.

AB - Substantial 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.

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

Abstract

ASJC Scopus subject areas

UN SDGs

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