Akt-dependent regulation of NF-κB is controlled by mTOR and Raptor in association with IKK

TLDR

NF‑κB drives cancer development, yet its activation mechanisms remain unclear; the oncogenic kinase Akt, often hyperactivated by PI3K mutations, PTEN loss, or growth‑factor signaling, signals through the effector mTOR. In PTEN‑deficient prostate cancer cells, Akt‑dependent mTOR, via Raptor, activates NF‑κB by stimulating IKK, and rapamycin blocks this pathway, highlighting Akt/mTOR’s role in gene expression and rapamycin’s therapeutic action.

Abstract

While NF-κB is considered to play key roles in the development and progression of many cancers, the mechanisms whereby this transcription factor is activated in cancer are poorly understood. A key oncoprotein in a variety of cancers is the serine–threonine kinase Akt, which can be activated by mutations in PI3K, by loss of expression/activity of PTEN, or through signaling induced by growth factors and their receptors. A key effector of Akt-induced signaling is the regulatory protein mTOR (mammalian target of rapamycin). We show here that mTOR downstream from Akt controls NF-κB activity in PTEN-null/inactive prostate cancer cells via interaction with and stimulation of IKK. The mTOR-associated protein Raptor is required for the ability of Akt to induce NF-κB activity. Correspondingly, the mTOR inhibitor rapamycin is shown to suppress IKK activity in PTEN-deficient prostate cancer cells through a mechanism that may involve dissociation of Raptor from mTOR. The results provide insight into the effects of Akt/mTOR-dependent signaling on gene expression and into the therapeutic action of rapamycin.