IKKβ Suppression of TSC1 Links Inflammation and Tumor Angiogenesis via the mTOR Pathway

Dung Fang Lee; Hsu Ping Kuo; Chun Te Chen; Jung Mao Hsu; Chao Kai Chou; Yongkun Wei; Hui Lung Sun; Long Yuan Li; Bo Ping; Wei Chien Huang; Xianghuo He; Jen Yu Hung; Chien Chen Lai; Qingqing Ding; Jen Liang Su; Jer Yen Yang; Aysegul A. Sahin; Gabriel N. Hortobagyi; Fuu Jen Tsai; Chang Hai Tsai; Mien Chie Hung

doi:10.1016/j.cell.2007.05.058

IKKβ Suppression of TSC1 Links Inflammation and Tumor Angiogenesis via the mTOR Pathway

Dung Fang Lee, Hsu Ping Kuo, Chun Te Chen, Jung Mao Hsu, Chao Kai Chou, Yongkun Wei, Hui Lung Sun, Long Yuan Li, Bo Ping, Wei Chien Huang, Xianghuo He, Jen Yu Hung, Chien Chen Lai, Qingqing Ding, Jen Liang Su, Jer Yen Yang, Aysegul A. Sahin, Gabriel N. Hortobagyi, Fuu Jen Tsai, Chang Hai TsaiMien Chie Hung

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

556 Scopus citations

Abstract

TNFα has recently emerged as a regulator linking inflammation to cancer pathogenesis, but the detailed cellular and molecular mechanisms underlying this link remain to be elucidated. The tuberous sclerosis 1 (TSC1)/TSC2 tumor suppressor complex serves as a repressor of the mTOR pathway, and disruption of TSC1/TSC2 complex function may contribute to tumorigenesis. Here we show that IKKβ, a major downstream kinase in the TNFα signaling pathway, physically interacts with and phosphorylates TSC1 at Ser487 and Ser511, resulting in suppression of TSC1. The IKKβ-mediated TSC1 suppression activates the mTOR pathway, enhances angiogenesis, and results in tumor development. We further find that expression of activated IKKβ is associated with TSC1 Ser511 phosphorylation and VEGF production in multiple tumor types and correlates with poor clinical outcome of breast cancer patients. Our findings identify a pathway that is critical for inflammation-mediated tumor angiogenesis and may provide a target for clinical intervention in human cancer.

Original language	English (US)
Pages (from-to)	440-455
Number of pages	16
Journal	Cell
Volume	130
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2007.05.058
State	Published - Aug 10 2007

Keywords

CELLBIO
HUMDISEASE
SIGNALING

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2007.05.058

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Lee, D. F., Kuo, H. P., Chen, C. T., Hsu, J. M., Chou, C. K., Wei, Y., Sun, H. L., Li, L. Y., Ping, B., Huang, W. C., He, X., Hung, J. Y., Lai, C. C., Ding, Q., Su, J. L., Yang, J. Y., Sahin, A. A., Hortobagyi, G. N., Tsai, F. J., ... Hung, M. C. (2007). IKKβ Suppression of TSC1 Links Inflammation and Tumor Angiogenesis via the mTOR Pathway. Cell, 130(3), 440-455. https://doi.org/10.1016/j.cell.2007.05.058

Lee, DF, Kuo, HP, Chen, CT, Hsu, JM, Chou, CK, Wei, Y, Sun, HL, Li, LY, Ping, B, Huang, WC, He, X, Hung, JY, Lai, CC, Ding, Q, Su, JL, Yang, JY, Sahin, AA, Hortobagyi, GN, Tsai, FJ, Tsai, CH & Hung, MC 2007, 'IKKβ Suppression of TSC1 Links Inflammation and Tumor Angiogenesis via the mTOR Pathway', Cell, vol. 130, no. 3, pp. 440-455. https://doi.org/10.1016/j.cell.2007.05.058

@article{bb7b09821a664ad0b2178799f504a53b,

title = "IKKβ Suppression of TSC1 Links Inflammation and Tumor Angiogenesis via the mTOR Pathway",

abstract = "TNFα has recently emerged as a regulator linking inflammation to cancer pathogenesis, but the detailed cellular and molecular mechanisms underlying this link remain to be elucidated. The tuberous sclerosis 1 (TSC1)/TSC2 tumor suppressor complex serves as a repressor of the mTOR pathway, and disruption of TSC1/TSC2 complex function may contribute to tumorigenesis. Here we show that IKKβ, a major downstream kinase in the TNFα signaling pathway, physically interacts with and phosphorylates TSC1 at Ser487 and Ser511, resulting in suppression of TSC1. The IKKβ-mediated TSC1 suppression activates the mTOR pathway, enhances angiogenesis, and results in tumor development. We further find that expression of activated IKKβ is associated with TSC1 Ser511 phosphorylation and VEGF production in multiple tumor types and correlates with poor clinical outcome of breast cancer patients. Our findings identify a pathway that is critical for inflammation-mediated tumor angiogenesis and may provide a target for clinical intervention in human cancer.",

keywords = "CELLBIO, HUMDISEASE, SIGNALING",

author = "Lee, {Dung Fang} and Kuo, {Hsu Ping} and Chen, {Chun Te} and Hsu, {Jung Mao} and Chou, {Chao Kai} and Yongkun Wei and Sun, {Hui Lung} and Li, {Long Yuan} and Bo Ping and Huang, {Wei Chien} and Xianghuo He and Hung, {Jen Yu} and Lai, {Chien Chen} and Qingqing Ding and Su, {Jen Liang} and Yang, {Jer Yen} and Sahin, {Aysegul A.} and Hortobagyi, {Gabriel N.} and Tsai, {Fuu Jen} and Tsai, {Chang Hai} and Hung, {Mien Chie}",

note = "Funding Information: We thank Drs. J. Blenis, E.J. Brown, P. Chiao, K.-L. Guan, K.-T. Jeang, D.J. Kwiatkowski, X. Lin, M. Karin, S.L. Schreiber, S.-C. Sun, G. Thomas, and Y. Xiong for providing reagents; Dr. E.W. McIntush from Bethyl Laboratory for generating antibodies; Dr. C.L. Walker, S. Zhang, J.G. Shi, B. Spohn, W. Xia, J.-F. Lee, R. Zhao, Y.-L. Lin, H.-W. Yeh, and L.-W. Huang for technical support; and Drs. S. Miller, S. Deming, P. Lo, and M. Worley for editing. This work was partially supported by National Institutes of Health grants RO1 CA058880, R01 CA109311, PO1 CA099031, Kadoorie Charitable Foundations, and National Breast Cancer Foundation, Inc. to M.-C.H; NIH MDACC SPORE in Breast Cancer CA116199, the Cancer Center support grant CA16672, and Breast Cancer Research Foundation grant to M.-C.H. and G.N.H.; a predoctoral fellowship from the US Army Breast Cancer Research Program, grant W81XWH-05-1-0252, and T.C. Hsu Endowed Memorial Scholarship and Andrew Sowell-Wade Huggins Scholarship from The University of Texas Graduate School of Biomedical Sciences at Houston to D.-F.L.; a predoctoral fellowship from the US Army Breast Cancer Research Program, grant W81XWH-06-1-0709 to C.-K.C; Taiwan Merit Scholarship from National Science Council of Taiwan to H.-L.S. and W.-C.H.; and Odyssey Scholarship from M.D. Anderson Cancer Center to J.-L.S. ",

year = "2007",

month = aug,

day = "10",

doi = "10.1016/j.cell.2007.05.058",

language = "English (US)",

volume = "130",

pages = "440--455",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - IKKβ Suppression of TSC1 Links Inflammation and Tumor Angiogenesis via the mTOR Pathway

AU - Lee, Dung Fang

AU - Kuo, Hsu Ping

AU - Chen, Chun Te

AU - Hsu, Jung Mao

AU - Chou, Chao Kai

AU - Wei, Yongkun

AU - Sun, Hui Lung

AU - Li, Long Yuan

AU - Ping, Bo

AU - Huang, Wei Chien

AU - He, Xianghuo

AU - Hung, Jen Yu

AU - Lai, Chien Chen

AU - Ding, Qingqing

AU - Su, Jen Liang

AU - Yang, Jer Yen

AU - Sahin, Aysegul A.

AU - Hortobagyi, Gabriel N.

AU - Tsai, Fuu Jen

AU - Tsai, Chang Hai

AU - Hung, Mien Chie

N1 - Funding Information: We thank Drs. J. Blenis, E.J. Brown, P. Chiao, K.-L. Guan, K.-T. Jeang, D.J. Kwiatkowski, X. Lin, M. Karin, S.L. Schreiber, S.-C. Sun, G. Thomas, and Y. Xiong for providing reagents; Dr. E.W. McIntush from Bethyl Laboratory for generating antibodies; Dr. C.L. Walker, S. Zhang, J.G. Shi, B. Spohn, W. Xia, J.-F. Lee, R. Zhao, Y.-L. Lin, H.-W. Yeh, and L.-W. Huang for technical support; and Drs. S. Miller, S. Deming, P. Lo, and M. Worley for editing. This work was partially supported by National Institutes of Health grants RO1 CA058880, R01 CA109311, PO1 CA099031, Kadoorie Charitable Foundations, and National Breast Cancer Foundation, Inc. to M.-C.H; NIH MDACC SPORE in Breast Cancer CA116199, the Cancer Center support grant CA16672, and Breast Cancer Research Foundation grant to M.-C.H. and G.N.H.; a predoctoral fellowship from the US Army Breast Cancer Research Program, grant W81XWH-05-1-0252, and T.C. Hsu Endowed Memorial Scholarship and Andrew Sowell-Wade Huggins Scholarship from The University of Texas Graduate School of Biomedical Sciences at Houston to D.-F.L.; a predoctoral fellowship from the US Army Breast Cancer Research Program, grant W81XWH-06-1-0709 to C.-K.C; Taiwan Merit Scholarship from National Science Council of Taiwan to H.-L.S. and W.-C.H.; and Odyssey Scholarship from M.D. Anderson Cancer Center to J.-L.S.

PY - 2007/8/10

Y1 - 2007/8/10

N2 - TNFα has recently emerged as a regulator linking inflammation to cancer pathogenesis, but the detailed cellular and molecular mechanisms underlying this link remain to be elucidated. The tuberous sclerosis 1 (TSC1)/TSC2 tumor suppressor complex serves as a repressor of the mTOR pathway, and disruption of TSC1/TSC2 complex function may contribute to tumorigenesis. Here we show that IKKβ, a major downstream kinase in the TNFα signaling pathway, physically interacts with and phosphorylates TSC1 at Ser487 and Ser511, resulting in suppression of TSC1. The IKKβ-mediated TSC1 suppression activates the mTOR pathway, enhances angiogenesis, and results in tumor development. We further find that expression of activated IKKβ is associated with TSC1 Ser511 phosphorylation and VEGF production in multiple tumor types and correlates with poor clinical outcome of breast cancer patients. Our findings identify a pathway that is critical for inflammation-mediated tumor angiogenesis and may provide a target for clinical intervention in human cancer.

AB - TNFα has recently emerged as a regulator linking inflammation to cancer pathogenesis, but the detailed cellular and molecular mechanisms underlying this link remain to be elucidated. The tuberous sclerosis 1 (TSC1)/TSC2 tumor suppressor complex serves as a repressor of the mTOR pathway, and disruption of TSC1/TSC2 complex function may contribute to tumorigenesis. Here we show that IKKβ, a major downstream kinase in the TNFα signaling pathway, physically interacts with and phosphorylates TSC1 at Ser487 and Ser511, resulting in suppression of TSC1. The IKKβ-mediated TSC1 suppression activates the mTOR pathway, enhances angiogenesis, and results in tumor development. We further find that expression of activated IKKβ is associated with TSC1 Ser511 phosphorylation and VEGF production in multiple tumor types and correlates with poor clinical outcome of breast cancer patients. Our findings identify a pathway that is critical for inflammation-mediated tumor angiogenesis and may provide a target for clinical intervention in human cancer.

KW - CELLBIO

KW - HUMDISEASE

KW - SIGNALING

UR - http://www.scopus.com/inward/record.url?scp=34547605613&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547605613&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2007.05.058

DO - 10.1016/j.cell.2007.05.058

M3 - Article

C2 - 17693255

AN - SCOPUS:34547605613

SN - 0092-8674

VL - 130

SP - 440

EP - 455

JO - Cell

JF - Cell

IS - 3

ER -

IKKβ Suppression of TSC1 Links Inflammation and Tumor Angiogenesis via the mTOR Pathway

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