Abstract
Nuclear factor kappaB (NF-kappaB) transcriptionally activates genes that promote immunity and cell survival. Activation of NF-kappaB is induced by an IkappaB kinase (IKK) complex that phosphorylates and promotes dissociation of IkappaB from NF-kappaB, which then translocates into the nucleus. Activation of phosphatidylinositol (PI) 3-kinase/Akt signaling by tumor necrosis factor (TNF) activates IKK and NF-kappaB. The present study shows that PTEN, a tumor suppressor that inhibits PI 3-kinase function, impairs TNF activation of Akt and the IKK complex in 293 cells. Transient expression of PTEN suppressed IKK activation and TNF-induced NF-kappaB DNA binding and transactivation. Studies were conducted with PC-3 prostate cancer cells that do not express PTEN and DU145 prostate cancer cells that express PTEN. TNF activated Akt in PC-3 cells, but not in DU145 cells, and the ability of TNF to activate NF-kappaB was blocked by pharmacological inhibition of PI 3-kinase activity in PC-3 cells, but not in DU145 cells. Expression of PTEN in PC-3 cells to a level comparable with that endogenously present in DU145 cells inhibited TNF activation of NF-kappaB. The cell type-specific ability of PTEN to negatively regulate the PI 3-kinase/AKT/NF-kappaB pathway may be important to its tumor suppressor activity.
Highlights
tumor necrosis factor (TNF)-␣1 is a pleiotropic cytokine that promotes immunity, fibroblast proliferation and wound repair, insulin resistance, and the syndrome of wasting and malnutrition known as cachexia in some chronic diseases [1,2,3]
Because our previous work showed that TNF activates a PI 3-kinase/Akt signaling pathway that plays a role in activation of Nuclear factor B (NF-B) in 293 embryonic kidney cells, we determined whether PTEN would inhibit this process. 293 cells transfected with an empty vector or PTEN were stimulated with TNF
Basal Akt activity was diminished in cells overexpressing PTEN, and the capacity of TNF to activate Akt above the basal level was abrogated by transient PTEN expression
Summary
TNF-␣1 is a pleiotropic cytokine that promotes immunity, fibroblast proliferation and wound repair, insulin resistance, and the syndrome of wasting and malnutrition known as cachexia in some chronic diseases [1,2,3]. The present study shows that PTEN, a tumor suppressor that inhibits PI 3-kinase function, impairs TNF activation of Akt and the IKK complex in 293 cells. Transient expression of PTEN suppressed IKK activation and TNF-induced NF-B DNA binding and transactivation.
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