Abstract
Activation of IKK enhances NF-κB signaling to facilitate cancer cell migration, invasion and metastasis. Here, we uncover the existence of a negative feedback loop of IKK. The transcription factor PATZ1 induces protein phosphatase-4 (PP4) regulatory subunit 2 (PP4R2) in an IKK-dependent manner. PP4R2 enhances the binding of PP4 to phosphorylated IKK to inactivate IKK/NF-κB signaling during sustained stimulation by cellular stimuli such as growth factors and inflammatory mediators. Matched pair studies reveal that primary lung cancers express more PATZ1 and PP4R2 than lymph node metastases in patients. Ectopic PATZ1 decreases invasion/colonization of lung cancers and prolongs the survival of xenograft mice. These effects of PATZ1 are reversed by downregulating PP4R2. Our results suggest that PATZ1 and PP4R2 provide negative feedback on IKK/NF-κB signaling to prevent cancer cells from over-stimulation from cellular stimuli; a decline in PATZ1 and PP4R2 is functionally associated with cancer migration/invasion and agents enhancing PATZ1 and PP4R2 are worth exploring to prevent invasion/metastasis of lung cancers.
Highlights
R Growth factors, inflammatory cytokines, pathogens and cellular stresses enhance NF-κB activity that regulates many target genes resulting in a variety of cellular responses [1]
Our results showed that the median levels of PATZ1 and PP4R2 were higher in primary tumors
T found that PP4R2 rather than PP4R1was increased in a variety of lung cancer cells under growth factor or PGE2 stimulation (Figure 1, 2 and Supplementary Figure S1, S2, and S3)
Summary
R Growth factors, inflammatory cytokines, pathogens and cellular stresses enhance NF-κB activity that regulates many target genes resulting in a variety of cellular responses [1]. The inhibitory effect of IκB on NF-κB is in turn suppressed by the phosphorylated IκB kinase (phospho-IKK) that. The PGE2-mediated increase of phospho-AktS473 dissipates within 2 h and reappears late after 12 h [6]. The resurgence of phospho-AktS473 is due to migrationinducing factor 7 (MIG-7)-mediated inactivation of protein phosphatase 2A (PP2A) [6]. It is not clear, whether this resurgence of phospho-AktS473 is accompanied by an increase in phosphorylated IKK and NF-κB p65
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