Editors' ChoiceCancer Biology

IKKβ Promotes Tumorigenesis

Science's STKE  14 Aug 2007:
Vol. 2007, Issue 399, pp. tw292
DOI: 10.1126/stke.3992007tw292

The tuberous sclerosis complex composed of TSC1 and TSC2, both tumor suppressors, inhibits the activity of the mTOR (mammalian target of rapamycin) pathway, which controls protein synthesis, cell proliferation, and production of vascular endothelial growth factor (VEGF). Lee et al. report that inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β, stimulate the mTOR pathway (detected as phosphorylation of the mTOR substrate S6K) in breast cancer cell lines and untransformed mammary epithelial cells. Activation of the mTOR pathway by TNF-α was lost if activity of inhibitor of nuclear factor κB kinase β (IKKβ) was decreased pharmacologically or by transfection of a dominant-negative inhibitor, by siRNA-mediated knockdown, or in Ikkβ knockout cells. IKKβ was not required for stimulation of mTOR signaling by growth factors or mitogens. IKKβ directly interacted with TSC1 and phosphorylated TSC1 on Ser487 and Ser511 both in vitro and in vivo. In cells expressing a mutant TSC1 [TSC1(SSAA)] in which the two serines were replaced with alanines, TNF-α failed to stimulate mTOR activity. Coimmunoprecipitation experiments with cells exposed to TNF-α suggested that phosphorylation by IKKβ disrupted the formation of the TSC1 and TSC2 complex, which is required for this complex to inhibit mTOR activity. In vivo tumorigenesis assays using TSC1 or TSC1(SSAA) or a phosphorylation mimic mutant [TSC1(SSDD)] showed that only wild-type TSC1 and TSC1(SSAA) had tumor-suppressing effects and that the blood vessel density of tumors with TSC1(SSDD) was higher than in the tumors with wild-type or TSC1(SSAA). Wild-type and TSC1(SSAA), but not TSC1(SSDD), exhibited the antiangiogenic effect of decreasing VEGF secretion when transfected into cultured cells. Thus, IKKβ-mediated inactivation of TSC1 may be one mechanism by which inflammation contributes to cancer progression. Phosphorylation of TSC1 at Ser511 correlated with breast cancer tumors that were also high in phosphorylated (and active) IKKβ and high in TNF-α. Additionally, breast tumor samples with high phosphorylated TSC1 (Ser511) and high phosphorylated S6K were associated with poor survival. Thus, this inflammatory connection appears to be an important aspect to cancer prognosis.

D.-F. Lee, H.-P. Kuo, C.-T. Chen, J.-M. Hsu, C.-K. Chou, Y. Wei, H.-L. Sun, L.-Y. Li, B. Ping, W.-C. Huang, X. He, J.-Y. Hung, C.-C. Lai, Q. Ding, J.-L. Su, J.-Y. Yang, A. A. Sahin, G. N. Hortobagyi, F.-J. Tsai, C.-H. Tsai, M.-C. Hung, IKKβ suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130, 440-455 (2007). [Online Journal]