Curcumin mediates ceramide generation via the de novo pathway in colon cancer cells

Abstract

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 are 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, the 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.

Chemo-resistant melanoma sensitized by tamoxifen to low dose curcumin treatment through induction of apoptosis and autophagy

“…Curcumin-induced apoptosis was also found to be associated with ROS generation in colon cancer (HT29 and HCT116) cells, hepatomas (Hep 3B and HepG2), submandibular carcinoma and a transformed human skin cancer cell line (COLO16). [6][7][8][9] Curcumin has been shown to generate ROS that resulted in mitochondrial DNA (mtDNA) damage in HepG2 cells. 10 Melanoma, along with cervical, prostate, lung and kidney cancer cell lines, exhibit resistance to the cytotoxic effects of curcumin treatment.…”

Monitoring Changes in the Oligomeric State of a Candidate Endoplasmic Reticulum (ER) Ceramide Sensor by Single-molecule Photobleaching

“…These assemblies bear striking analogy with the helical polymers formed by DGK␦-SAM, which comprise six monomers per turn (23). Moreover, treatment of cells with curcumin, a drug known to deregulate ceramide and calcium levels in the ER (25,26), promotes formation of SMSr hexamers 4 ( Fig. 1).…”

“…Curcumin Promotes meGFP-SMSr Homo-oligomerization in the ER-We recently observed that curcumin, a drug known to deregulate ceramide and calcium levels in the ER (25,26), promotes self-assembly of SMSr into hexamers. 4 Although this effect appears to be independent of fluctuations in ER ceramide or calcium levels and may potentially involve a curcumin-associated cross-linking activity (33), the underlying mechanism remains to be established.…”

The effects of Curcuma longa and curcumin on reproductive systems

“…Recently, the curcumin has been shown to induce ceramide generation to stimulate cancer cell apoptosis (Moussavi et al 2006). It seems that increasing agents of the intracellular ceramide levels could enhance tumor cell cytotoxicity and apoptosis caused by curcumin (Yu et al 2012).…”