Down-regulation of the Tumor Suppressor PTEN by the Tumor Necrosis Factor-α/Nuclear Factor-κB (NF-κB)-inducing Kinase/ NF-κB Pathway Is Linked to a Default IκB-α Autoregulatory Loop

Abstract

The PTEN (phosphatase and tensin homolog deleted on chromosome ten) tumor suppressor gene affects multiple cellular processes including cell growth, proliferation, and cell migration by antagonizing phosphatidylinositol 3-kinase (PI3K). However, mechanisms by which PTEN expression is regulated have not been studied extensively. Similar to PTEN, tumor necrosis factor-α (TNF-α) affects a wide spectrum of diseases including inflammatory processes and cancer by acting as a mediator of apoptosis, inflammation, and immunity. In this study, we show that treatment of cancer cell lines with TNF-α decreases PTEN expression. In addition, overexpression of TNF-α downstream signaling targets, nuclear factor-κB (NF-κB)-inducing kinase (NIK) and p65 nuclear factor NF-κB, lowers PTEN expression, suggesting that TNF-α-induced down-regulation of PTEN is mediated through a TNF-α/NIK/NF-κB pathway. Down-regulation of PTEN by NIK/NF-κB results in activation of the PI3K/Akt pathway and augmentation of TNF-α-induced PI3K/Akt stimulation. Importantly, we demonstrate that this effect is associated with a lack of an inhibitor of κB (IκB)-α autoregulatory loop. Moreover, these findings suggest the interaction between PI3K/Akt and NF-κB via transcriptional regulation of PTEN and offer one possible explanation for increased tumorigenesis in systems in which NF-κB is chronically activated. In such a tumor system, these findings suggest a positive feedback loop whereby Akt activation of NF-κB further stimulates Akt via down-regulation of the PI3K inhibitor PTEN.