Life and death in cancer: GADD45 α and γ are critical regulators of NF-κB mediated escape from programmed cell death

Abstract

The NF-κB/IκB signaling pathway is a critical regulator of cell survival, and constitutive activation of NF-κB is a crucial step for many types of cancers to escape programmed cell death. Furthermore, chemotherapeutic agents activate NF-κB in cancer cells, and this may partially explain the resistance of cancer cells to chemotherapy. The precise mechanism of the anti-apoptotic action of NF-κB is not known, but involves the regulation of several cell cycle regulatory and anti-apoptotic genes. We recently demonstrated that NF-κB mediated cell survival is absolutely dependent on two GADD45 family members, GADD45α and γ. In line with this, inhibition of NF-κB in cancer cells results in GADD45α and g dependent induction of apoptosis, JNK activation and inhibition of tumor growth. These findings establish an unambiguous role for the GADD45 family as an essential mediator of cell survival in cancer cells with implications for cancer chemotherapy and novel drug discovery. ©2005 Landes Bioscience.