IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway.
TNFalpha 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 IKKbeta, a major downstream kinase in the TNFalpha signaling pathway, physically interacts with and phosphorylates TSC1 at Ser487 and Ser511, resulting in suppression of TSC1. The IKKbeta-mediated TSC1 suppression activates the mTOR pathway, enhances angiogenesis, and results in tumor development. We further find that expression of activated IKKbeta 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.
Lee
Dung-Fang
DF
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Kuo
Hsu-Ping
HP
Chen
Chun-Te
CT
Hsu
Jung-Mao
JM
Chou
Chao-Kai
CK
Wei
Yongkun
Y
Sun
Hui-Lung
HL
Li
Long-Yuan
LY
Ping
Bo
B
Huang
Wei-Chien
WC
He
Xianghuo
X
Hung
Jen-Yu
JY
Lai
Chien-Chen
CC
Ding
Qingqing
Q
Su
Jen-Liang
JL
Yang
Jer-Yen
JY
Sahin
Aysegul A
AA
Hortobagyi
Gabriel N
GN
Tsai
Fuu-Jen
FJ
Tsai
Chang-Hai
CH
Hung
Mien-Chie
MC
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D018836:Inflammation Mediators / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D018836:Inflammation Mediators; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase