Carcinogenesis Advance Access published online on July 22, 2004
Carcinogenesis, doi:10.1093/carcin/bgh239
© 2004 by Oxford University Press
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1 Cellular and Molecular Nutrition Research Laboratory, Graduate Program in Nutrition, The University of North Carolina at Greensboro, Greensboro, NC 27402-6170, USA
* To whom correspondence should be addressed. E-mail: g_loo{at}uncg.edu.
Ingestion of plant products containing the phenolic phytochemical, curcumin, has been linked to lower incidences of colon cancer, suggesting that curcumin has cancer chemopreventive effects. Supporting this suggestion at the cellular level, apoptosis occurs in human colon cancer cells exposed to curcumin. However, the mechanism is unclear, prompting this investigation to further clarify the molecular effects of curcumin. HCT-116 colonocytes were incubated with 0-20 µM curcumin for 0-48 hrs. In concentration-dependent and time-dependent manners, curcumin induced DNA damage, resulting later in the appearance of cellular features characteristic of apoptosis. To identify a potential pro-apoptotic gene that could be responsive to the DNA damage in curcumin-treated cells, Growth Arrest and DNA Damage-inducible gene 153 (GADD153) was considered. Curcumin increased GADD153 mRNA (and also protein) expression, which was prevented by actinomycin D and also by a broad PKC inhibitor, but not by selective MAPK inhibitors. These findings suggest that curcumin-induced upregulation of GADD153 mRNA expression was at the level of transcription, but apparently without depending on upstream MAPK. In determining the involvement of reactive oxygen species in mediating the effect of curcumin on GADD153, the antioxidants pyrrolidine dithiocarbamate and N-acetylcysteine (NAC), but neither
Revised July 7, 2004
Accepted July 18, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Curcumin-induced GADD153 gene upregulation in human colon cancer cells
Abstract 
-tocopherol nor catalase, also blunted or prevented upregulation of GADD153 mRNA expression caused by curcumin. Most noteworthy, when NAC was tested, it inhibited the DNA damage and apoptosis caused by curcumin. Because expression of GADD153 protein was detected before the appearance of apoptotic features, this observation raises the possibility that GADD153 protein might be important for curcumin-induced apoptosis.
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