Ceramide synthase 6 modulates TRAIL sensitivity and nuclear translocation of active caspase-3 in colon cancer cells

• Published in: Oncogene Vol. 28; no. 8; pp. 1132 - 1141
• Main Authors: White-Gilbertson, S, Mullen, T, Senkal, C, Lu, P, Ogretmen, B, Obeid, L, Voelkel-Johnson, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.02.2009; Nature Publishing Group
• Subjects: Ageing, cell death; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Care and treatment; Caspase 3 - metabolism; Caspase Inhibitors; Caspase-3; Cell Biology; Cell Nucleus - metabolism; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Ceramide; Ceramides - pharmacology; Colon cancer; Colonic Neoplasms - enzymology; Colonic Neoplasms - pathology; Colonic Neoplasms - secondary; Colorectal cancer; Enzyme Activation; Enzyme Inhibitors - pharmacology; Fumonisin B1; Fumonisins - pharmacology; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Genetic aspects; Genetics; Health aspects; Human Genetics; Humans; Inhibitor drugs; Internal Medicine; Ligands; Medical sciences; Medicine; Medicine & Public Health; Molecular and cellular biology; Nuclear transport; Oncology; original-article; Oxidoreductases - antagonists & inhibitors; Oxidoreductases - genetics; Oxidoreductases - metabolism; Permeability; Phenotypes; Physiological aspects; Protein Transport; RNA, Small Interfering - pharmacology; RNA-mediated interference; Sphingosine - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; TNF-Related Apoptosis-Inducing Ligand - genetics; TNF-Related Apoptosis-Inducing Ligand - metabolism; TRAIL protein; Tumor Cells, Cultured; Tumor necrosis factor; Tumors; United States; ceramide synthase; longevity assurance homologue; apoptosis; ceramide; TRAIL; Translocation; Enzyme; Caspase; Malignant tumor; Longevity; Synthase; Carcinogenesis; Colonic disease; Peptidases; Sensitivity; Colon cancer; Ceramide; Hydrolases; Digestive diseases; Intestinal disease; Cancer; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2008.468

We have previously shown that the death receptor ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces an increase of intracellular C 16 -ceramide in sensitive SW480 but not in resistant SW620 cells. Resistance in SW620 cells was overcome by exogenous ceramide, leading us to propose that defective ceramide signaling contributes to TRAIL resistance. In this study we found that the increase in C 16 -ceramide in SW480 cells was inhibited by fumonisin B1, an inhibitor of ceramide synthases (CerS). Protein analysis revealed that TRAIL-resistant SW620 cells expressed lower levels of ceramide synthase 6 (CerS6, also known as longevity assurance homologue 6), which prompted us to investigate the effect of CerS6 modulation on TRAIL phenotype. RNAi against CerS6 resulted in a specific and significant decrease of the C 16 -ceramide species, which was sufficient to inhibit TRAIL-induced apoptosis. In cells with decreased levels of CerS6, caspase-3 was activated but failed to translocate into the nucleus. CerS6 localized primarily to the perinuclear region, suggesting this enzyme may be important in regulation of nuclear permeability. Moderate elevation in CerS6 expression was sufficient to reverse TRAIL resistance in SW620 cells. These results suggest that modulation of CerS6 expression may constitute a new therapeutic strategy to alter apoptotic susceptibility.