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Ceramide mediates tumor-induced dendritic cell apoptosis
T Kanto1, P Kalinski, O C Hunter
1Department of Surgery, Division of Biologic Therapeutics and Surgical Oncology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|September 21, 2001
Summary
Tumor cells induce dendritic cell (DC) apoptosis by increasing ceramide levels, which inhibits survival signals. This ceramide accumulation down-regulates the phosphoinositide 3-kinase (PI3K) pathway, leading to DC death and immune evasion.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Tumor cells evade immune surveillance partly by inducing apoptosis in dendritic cells (DCs).
- Understanding the mechanisms of tumor-induced DC apoptosis is crucial for developing cancer immunotherapies.
Purpose of the Study:
- To elucidate the molecular mechanisms by which tumor cells induce apoptosis in dendritic cells.
- To investigate the role of ceramide and the phosphoinositide 3-kinase (PI3K) pathway in this process.
Main Methods:
- Analysis of ceramide levels in DCs using electrospray mass spectrometry.
- Induction of apoptosis in bone marrow-derived DCs using tumor cell supernatants (SN).
- Pharmacological manipulation of ceramide synthesis and PI3K pathway activity.
Main Results:
- Tumor SN increased ceramide levels (C16 and C24) and induced DC apoptosis.
- Inhibitors of ceramide metabolism (N-oleoylethanolamine, PDMP) enhanced DC apoptosis and ceramide levels.
- Inhibitors of ceramide synthesis (L-cycloserine) and a PI3K activator (12-O-tetradecanoylphorbol-13-acetate) protected DCs from apoptosis.
- Tumor SN, N-oleoylethanolamine, and PDMP suppressed Akt, NF-kappaB, and bcl-x(L), indicating PI3K pathway inhibition.
Conclusions:
- Ceramide accumulation mediates tumor-induced DC apoptosis by down-regulating the PI3K pathway.
- Targeting ceramide metabolism or the PI3K pathway may offer strategies to enhance anti-tumor immunity.