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

Abstract

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.

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

“…In addition, colocalization of caveolin-1 and b-catenin was observed (Figure 4a). Therefore, overexpression of caveolin-1 might stabilize the E-cadherin/b-catenin complex on membranes by suppressing the phosphorylation of b-catenin, which negatively regulate the interaction between E-cadherin and b-catenin (Piedra et al, 2003;Lee et al, 2007;Tominaga et al, 2008).…”

NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer

“…Similar to IKK-dependent but NF-κB transcription independent control of metastasis, there is also a specifi c link between IKK and angiogenesis. It has been showed that IKKβ upregulates mTOR activity through direct phosphorylation of TSK1 at ser487 and ser511 (Lee et al, 2007).…”

mTOR signaling: PLD takes center stage

“…For instance, TSC and PLD are both modulated by mitogens (e.g., serum and insulin) [40][41][42][43][44][45][46] and TNFα. 15,47 The Ras-Raf-MEK-Erk pathway inhibits TSC2 via phosphorylation by either Erk 48,49 or a downstream kinase Rsk, 50 at the same time PLD activation by Ras [51][52][53][54] or Erk 54,55 has also been suggested. Most recently, our studies have uncovered a direct interaction between Rheb and PLD1.…”

“…11 In recent years, the TSC1/TSC2 complex has emerged as a master regulator of mTORC1 signaling in cell growth by serving as a hub for receiving multiple upstream signals, 12,13 including mitogenic stimulation, cellular energy deprivation, hypoxia, inflammatory signals, and oncogenic Wnt signaling [1][2][3][4]14,15 (Fig. 1).…”