The PTEN tumor suppressor gene modulates cell growth and survival known to be regulated by the activation of the transcription factor NF kappa B. suggesting PTEN might affect the NF kappa B activation pathway. We found that PTEN inhibited NF kappa B activation induced by TNF. The suppression of NF kappa B activation correlated with sequential inhibition of the tumor necrosis factor-induced expression of NF kappa B-regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin) gene products. Downregulation of the antiapoptotic genes by PTEN increased TNF-induced apoptosis, as indicated by caspase activation, TUNEL, annexin staining, and esterase assay. We conclude that the ectopic expression of PTEN enhances TNF-induced apoptosis and downregulates the proliferation of glioma cells through the suppression of various molecules including NF kappa B, and various mediators of cellular survival and proliferation, and that this targets might be essential for its central role in the growth and survival of glioma cancer cells. (c) 2006 Elsevier Inc. All rights reserved.