Carcinogenesis Advance Access published online on February 25, 2006
Carcinogenesis, doi:10.1093/carcin/bgi371
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1 The Jack Bell Research Centre, 2660 Oak Street, and Vancouver, BC, Canada
* To whom correspondence should be addressed. A wealth of evidence supports the notion that curcumin, a phytochemical present in turmeric, is a potent chemopreventive agent for colon cancer. Its mechanism of action remains incompletely understood. Here we report that curcumin's apoptosis-inducing effects in colon cancer cell lines is accompanied by robust ceramide generation. This occurs through de novo synthesis as the increase in ceramide could be attenuated by pre-incubation of the cells with myriocin, and no changes were observed in sphingomyelin levels, or in either acidic or neutral sphingomyelinase activities. Furthermore, cell death could in part be reversed by myriocin, indicating, for the first time, that endogenous ceramide generation by this agent contributes towards its biological activity. We then investigated the role of reactive oxygen species (ROS) in this phenomenon and demonstrated that curcumin induced robust oxidant generation in the cell lines tested, and its reversal by N-acetylcysteine, completely attenuated apoptosis. We next confirmed that curcumin could activate c-jun N-terminal kinase (JNK) and that its modulation could reverse cell death, however this intervention could not block ceramide generation, or ROS production. Conversely however, inhibition of ROS using N-acetylcysteine led to an inhibition of JNK activation. Hence we conclude that curcumin induces apoptosis via a ROS-associated mechanism that converges on JNK activation, and to a lesser extent via a parallel ceramide-associated pathway.
Received September 9, 2005
Revised January 14, 2006
Accepted February 11, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Curcumin mediates ceramide generation via the de novo pathway in colon cancer cells
Maryam Moussavi 1,
Kiran Assi 1,
Antonio Gómez-Muñoz 2,
and
Baljinder Salh 1 *
2 Current address: Department of Biochemistry and Molecular Biology, Faculty of Science, University of the Basque Country, P. O. Box 644, 48080 Bilbao, Spain
Baljinder Salh, E-mail: bsalh{at}interchange.ubc.ca
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