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Updated: Jun 20, 2026
Saturated Fatty Acids Induce Ceramide-associated Macrophage Cell Death
Published on: October 31, 2017
Lysosomal ceramide mediates gemcitabine-induced death of glioma cells
Claudia A Dumitru1, Ibrahim E Sandalcioglu, Marek Wagner
1Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
Abstract:
Acid sphingomyelinase-induced ceramide release has been shown by many studies to induce apoptosis in response to various stimuli. However, the mechanisms of acid sphingomyelinase/ceramide-mediated death signaling following treatment with chemotherapeutic drugs have not been fully elucidated thus far. The present study demonstrates that treatment of glioma cells with clinically achievable doses of gemcitabine results in acid sphingomyelinase activation, lysosomal accumulation of ceramide, cathepsin D activation, Bax insertion into the mitochondria, and cell death. Pharmacological inhibition or genetic deficiency of acid sphingomyelinase prevented these events while overexpression of the enzyme sensitized cells to gemcitabine. Likewise, inhibitors of lysosomal functions also prevent gemcitabine-induced cell death. Our data indicate a critical role of the acid sphingomyelinase/ceramide system for gemcitabine-induced signaling and suggest that lysosomal ceramide accumulation mediates cell death induced by a chemotherapeutic drug.
Insights
Gemcitabine triggers acid sphingomyelinase (ASM) activation, leading to ceramide accumulation and cell death in glioma cells. Inhibiting ASM or lysosomal function prevents this chemotherapy-induced apoptosis.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Acid sphingomyelinase (ASM)-mediated ceramide release is a known inducer of apoptosis.
- The precise mechanisms of ASM/ceramide signaling in chemotherapy-induced cell death remain unclear.
Purpose of the Study:
- To elucidate the role of the ASM/ceramide system in gemcitabine-induced apoptosis in glioma cells.
- To investigate the involvement of lysosomal pathways in this process.
Main Methods:
- Treatment of glioma cells with gemcitabine.
- Assessment of ASM activation, ceramide levels, cathepsin D activation, and Bax translocation.
- Utilized pharmacological inhibitors and genetic manipulation of ASM, as well as lysosomal inhibitors.
Main Results:
- Gemcitabine treatment activated ASM, causing lysosomal ceramide accumulation and subsequent cell death.
- Inhibition or genetic deficiency of ASM abolished gemcitabine-induced apoptosis.
- Overexpression of ASM enhanced sensitivity to gemcitabine.
- Inhibitors of lysosomal function also prevented gemcitabine-induced cell death.
Conclusions:
- The acid sphingomyelinase/ceramide system plays a critical role in gemcitabine-induced signaling.
- Lysosomal ceramide accumulation mediates chemotherapy-induced cell death, highlighting a potential therapeutic target.
