Role of WWOX and NF-κB in lung cancer progression

It is generally agreed that the pro-inflammatory, pro-survival transcription factor NF-κB is a tumor promoter. Tumor necrosis factor alpha (TNF-α or TNF) mediates NF-κB activation. Tumor suppressor WWOX (FOR or WOX1) is a downstream effector of the TNF signaling. Thus, activation of both WWOX (FOR or WOX1) and NF-κB may occur during TNF signaling and/or under stress conditions. Indeed, the first WW domain of WWOX induces the activation of NF-κB-responsive promoter without TNF participation. It appears that WWOX counteracts with NF-κB in regulating cell survival and death. For example, WWOX becomes activated with Tyr33 phosphorylation and relocates together with NF-κB and many transcription factors to the nucleus to cause neuronal death in sciatic nerve-transected rats. While WWOX is frequently lost in lung cancer and many other cancers, NF-κB activation-induced cancer promotion probably requires WWOX-independent signaling networks to induce expression of pro-survival factors. The antagonistic role of WWOX and NF-κB in the regulation of lung cancer progression is discussed.