Differential IKK/NF-kB Activity Is Mediated by TSC2 through mTORC1 in PTEN-Null Prostate Cancer and Tuberous Sclerosis Complex Tumor Cells

The serine/threonine protein kinase Akt plays a critical role in regulating proliferation, growth, and survival through phosphorylation of different downstream substrates. The mTOR is a key target for Akt to promote tumorigenesis. It has been reported that Akt activates mTOR through phosphorylation and inhibition of the tuberous sclerosis complex (TSC) protein TSC2. Previously, it was demonstrated that mTOR activates IKK/NF-kB signaling by promoting IkB kinase (IKK) activity downstream of Akt in conditions deficient of PTEN. In this study, the mechanistic role of the tumor-suppressor TSC2 was investigated in the regulation of IKK/NF-kB activity in PTENnull prostate cancer and in TSC2-mutated tumor cells. The results demonstrate that TSC2 inhibits IKK/NF-kB activity downstream of Akt and upstream of mTORC1 in a PTENdeficient environment. However, TSC2 promotes IKK/NF-kB activity upstream of Akt and mTORC1 in TSC2 mutated tumor cells. These data indicate that TSC2 negatively or positively regulates IKK/NF-kB activity in a context-dependent manner depending on the genetic background. Implications: This study provides fundamental insight for understanding the molecular details by which TSC2/mTOR regulates NF-kB signaling in different tumors. Mol Cancer Res; 1–13. 2015