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

By S. White-Gilbertson, T. Mullen, C. Senkal, Ping Lu, B. Ogretmen, LM Obeid, C. Voelkel-Johnson. 2009

151 citations recorded by the source corpus.

We have previously shown that the death receptor ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces an increase of intracellular C16-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 C16-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 C16-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.

Subfields: Cell Biology, Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

In Molecular Biology

Citations in the corpus

Mammalian Ceramide Synthases (2010, background): “intracellular C16-ceramide, and protected colon adenocarcinoma cells against TRAIL-mediated apoptosis and interfered with translocation of active caspase 3 into the nucleus, whereas increasing CerS6 expression sensitized the cells to TRAIL (79).”
Sorafenib and Vorinostat Kill Colon Cancer Cells by CD95-Dependent and -Independent Mechanisms (2009, background): “It has recently been shown that SW620 cells are refractory to death receptor signaling induced by tumor necrosis factor-related apoptosis-inducing ligand, which was linked to low expression of ceramide synthase 6 (LASS6), an enzyme in the de novo ceramide synthesis pathway, and with a lack of cerami”
Antiapoptotic roles of ceramide‐synthase‐6‐generated C16‐ceramide via selective regulation of the ATF6/ CHOP arm of ER‐stress‐response pathways (2010, background): “the proapoptotic role of ceramide (48) and suggest that”