NF-[kappa]B-mediated repression of growth arrest- and DNA-damage-inducible proteins 45 [alpha] and [gamma] is essential for cancer cell survival

The NF-[kappa]B/I[kappa]B signaling pathway is a critical regulator of cell survival in cancer. Here, we report that combined down-regulation of growth arrest- and DNA-damage-inducible proteins (GADD)45 [alpha] and [gamma] expression by NF-[kappa]B is an essential step for various cancer types to escape programmed cell death. We demonstrate that inhibition of NF-[kappa]B in cancer cells results in GADD45 [alpha]- and [gamma]-dependent induction of apoptosis and inhibition of tumor growth. Inhibition of GADD45 [alpha] and [gamma] in cancer cells by small interfering RNA abrogates apoptosis induction by the inhibitor of NF-[kappa]B and blocks c-Jun N-terminal kinase activation, whereas overexpression of GADD45 [alpha] and [gamma] activates c-Jun N-terminal kinase and induces apoptosis. These results 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.