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
Journal of Biological Chemistry
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-␣ (TNF-␣) affects a wide spectrum of diseases including inflammatory processes and cancer by acting as a mediator of apoptosis,
... or of apoptosis, inflammation, and immunity. In this study, we show that treatment of cancer cell lines with TNF-␣ decreases PTEN expression. In addition, overexpression of TNF-␣ downstream signaling targets, nuclear factor-B (NF-B)-inducing kinase (NIK) and p65 nuclear factor NF-B, lowers PTEN expression, suggesting that TNF-␣-induced down-regulation of PTEN is mediated through a TNF-␣/NIK/NF-B pathway. Down-regulation of PTEN by NIK/NF-B results in activation of the PI3K/Akt pathway and augmentation of TNF-␣-in- duced PI3K/Akt stimulation. Importantly, we demonstrate that this effect is associated with a lack of an inhibitor of B (IB)-␣ autoregulatory loop. Moreover, these findings suggest the interaction between PI3K/Akt and NF-B via transcriptional regulation of PTEN and offer one possible explanation for increased tumorigenesis in systems in which NF-B is chronically activated. In such a tumor system, these findings suggest a positive feedback loop whereby Akt activation of NF-B further stimulates Akt via down-regulation of the PI3K inhibitor PTEN.