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

ABSTRACT: The NF-kappaB/IkappaB 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)45alpha and gamma expression by NF-kappaB is an essential step for various cancer types to escape programmed cell death. We demonstrate that inhibition of NF-kappaB in cancer cells results in GADD45alpha- and gamma-dependent induction of apoptosis and inhibition of tumor growth. Inhibition of GADD45alpha and gamma in cancer cells by small interfering RNA abrogates apoptosis induction by the inhibitor of NF-kappaB and blocks c-Jun N-terminal kinase activation, whereas overexpression of GADD45alpha 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.

SUBMITTER: Zerbini LF 

PROVIDER: S-EPMC518803 | biostudies-other | 2004 Sep

REPOSITORIES: biostudies-other

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

Zerbini Luiz F LF   Wang Yihong Y   Czibere Akos A   Correa Ricardo G RG   Cho Je-Yoel JY   Ijiri Kosei K   Wei Wanjang W   Joseph Marie M   Gu Xuesong X   Grall Franck F   Goldring Mary B MB   Zhou Jin-Rong JR   Libermann Towia A TA  

Proceedings of the National Academy of Sciences of the United States of America 20040907 37

The NF-kappaB/IkappaB 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)45alpha and gamma expression by NF-kappaB is an essential step for various cancer types to escape programmed cell death. We demonstrate that inhibition of NF-kappaB in cancer cells results in GADD45alpha- and gamma-dependent induction of apoptosis and inhibition of tumor growth. Inhibition of GADD45alph  ...[more]