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

Ling LU, Tan KB, Lin H, Chiu GN - Cell Death Dis (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.

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.

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Proposed model depicting the mechanism of action of safingol in MDA-MB-231 and HT-29 cells
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fig8: Proposed model depicting the mechanism of action of safingol in MDA-MB-231 and HT-29 cells

Mentions: To our knowledge, this is the first report showing that ROS have a key role in safingol-treated human cancer cell lines, MDA-MB-231 and HT-29. Interestingly, such ROS production could also trigger autophagy, which appeared to be a repair mechanism. We have also shown that glucose uptake is inhibited by safingol, which is an event preceding ROS generation. On the basis of these findings, we propose a model depicting the possible mechanism of action of safingol in MDA-MB-231 and HT-29 cells (Figure 8).


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

Ling LU, Tan KB, Lin H, Chiu GN - Cell Death Dis (2011)

Proposed model depicting the mechanism of action of safingol in MDA-MB-231 and HT-29 cells
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3101809&req=5

fig8: Proposed model depicting the mechanism of action of safingol in MDA-MB-231 and HT-29 cells
Mentions: To our knowledge, this is the first report showing that ROS have a key role in safingol-treated human cancer cell lines, MDA-MB-231 and HT-29. Interestingly, such ROS production could also trigger autophagy, which appeared to be a repair mechanism. We have also shown that glucose uptake is inhibited by safingol, which is an event preceding ROS generation. On the basis of these findings, we propose a model depicting the possible mechanism of action of safingol in MDA-MB-231 and HT-29 cells (Figure 8).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.

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.

Show MeSH
Related in: MedlinePlus