The role of reactive oxygen species and autophagy in safingol-induced cell death.

Abstract

Safingol is a sphingolipid with promising anticancer potential, which is currently in phase I clinical trial. Yet, the underlying mechanisms of its action remain largely unknown. We reported here that safingol-induced primarily accidental necrotic cell death in MDA-MB-231 and HT-29 cells, as shown by the increase in the percentage of cells stained positive for 7-aminoactinomycin D, collapse of mitochondria membrane potential and depletion of intracellular ATP. Importantly, safingol treatment produced time- and concentration-dependent reactive oxygen species (ROS) generation. Autophagy was triggered following safingol treatment, as reflected by the formation of autophagosomes, acidic vacuoles, increased light chain 3-II and Atg biomarkers expression. Interestingly, scavenging ROS with N-acetyl-L-cysteine could prevent the autophagic features and reverse safingol-induced necrosis. Our data also suggested that autophagy was a cell repair mechanism, as suppression of autophagy by 3-methyladenine or bafilomycin A1 significantly augmented cell death on 2-5 μM safingol treatment. In addition, Bcl-xL and Bax might be involved in the regulation of safingol-induced autophagy. Finally, glucose uptake was shown to be inhibited by safingol treatment, which was associated with an increase in p-AMPK expression. Taken together, our data suggested that ROS was the mediator of safingol-induced cancer cell death, and autophagy is likely to be a mechanism triggered to repair damages from ROS generation on safingol treatment.

• Authors: L-U Ling, K-B Tan, H Lin, G N C Chiu
• Journal: Cell death & disease (Cell Death Dis) Vol. 2 Pg. e129 (Mar 10 2011) ISSN: 2041-4889 [Electronic] England
• PMID: 21390063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Reactive Oxygen Species
• Sphingosine
• safingol

Topics

• Autophagy (drug effects)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cells (cytology, drug effects, metabolism)
• HT29 Cells
• Humans
• Neoplasms (drug therapy, metabolism, physiopathology)
• Reactive Oxygen Species (metabolism)
• Sphingosine (analogs & derivatives, pharmacology)