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Up-regulation of GADD45α expression by NSAIDs leads to apoptotic and necrotic colon cancer cell deaths

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Abstract

Growth arrest and DNA damage inducible 45 alpha (GADD45α) is a central player in mediating apoptosis induced by a variety of stress stimuli and genotoxic agents. Regular usage of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and sulindac is associated with reduced risk for various cancers, including colon cancer. The role of GADD45α in NSAID-induced colon cancer cell cytotoxicity is unknown. In this study, we report that indomethacin and sulindac sulfide treatments up-regulate GADD45α mRNA expression and protein levels in colon cancer HT-29, RKO and Caco-2 cells. This up-regulation of GADD45α is accompanied by necrotic cell death and apoptosis. Anti-sense suppression of GADD45α expression inhibited indomethacin and sulindac sulfide-induced necrotic cell death and apoptosis. These findings confirm a role for GADD45α in NSAID-induced cytotoxicity, a mechanism for the anti-neoplastic effect of NSAIDs in colon tumorigenesis and cancer growth.

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Acknowledgements

This work was funded by the Department of Veterans Affairs Merit Review Grant and the Southern California Institute of Research and Education Small Grant to S.-K.C.

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  1. Department of Veterans Affairs Medical Center, 5901 E 7th St., Long Beach, CA, 90822-5201, USA

    Shiun-Kwei Chiou & Neil Hoa

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  1. Shiun-Kwei Chiou
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Correspondence to Shiun-Kwei Chiou.

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Chiou, SK., Hoa, N. Up-regulation of GADD45α expression by NSAIDs leads to apoptotic and necrotic colon cancer cell deaths. Apoptosis 14, 1341–1351 (2009). https://doi.org/10.1007/s10495-009-0399-6

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