The PTEN tumor suppressor protein inhibits tumor necrosis factor-induced nuclear factor kappa B activity

Nuclear factor kappaB (NF-kappaB) transcriptionally activates genes that pr omote immunity and cell survival. Activation of NF-kappaB is induced by an I kappaB kinase (IKK) complex that phosphorylates and promotes dissociation of I kappaB from NF-kappaB, which then translocates into the nucleus. Acti vation of phosphatidylinositol (PI) 3-kinase/Akt signaling by tumor necrosi s factor (TNF) activates IKK and NF-kappaB. The present study shows that PT EN, a tumor suppressor that inhibits PI 3-kinase function, impairs TNF acti vation of Akt and the IKK complex in 293 cells. Transient expression of PTE N suppressed IKK activation and TNF-induced NF-kappaB DNA binding and trans activation. Studies were conducted with PC-3 prostate cancer cells that do not express PTEN and DU145 prostate cancer cells that express PTEN. TNF act ivated 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-kinas e 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 P TEN to negatively regulate the PI 3-kinase/AKT/NF-kappaB pathway may be imp ortant to its tumor suppressor activity.