DHA-mediated enhancement of TRAIL-induced apoptosis in colon cancer cells is associated with engagement of mitochondria and specific alterations in sphingolipid metabolism
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24953781
DOI
10.1016/j.bbalip.2014.06.005
PII: S1388-1981(14)00116-4
Knihovny.cz E-resources
- Keywords
- Apoptosis, Colon cancer, Docosahexaenoic acid, Lipid metabolism, TRAIL,
- MeSH
- Adenocarcinoma genetics metabolism pathology MeSH
- Apoptosis drug effects genetics MeSH
- Cytochromes c metabolism MeSH
- Inhibitor of Apoptosis Proteins MeSH
- eIF-2 Kinase genetics metabolism MeSH
- Docosahexaenoic Acids pharmacology MeSH
- Humans MeSH
- Membrane Potential, Mitochondrial drug effects MeSH
- Mitochondria drug effects metabolism MeSH
- Cell Line, Tumor MeSH
- Colonic Neoplasms genetics metabolism pathology MeSH
- bcl-2 Homologous Antagonist-Killer Protein genetics metabolism MeSH
- TNF-Related Apoptosis-Inducing Ligand pharmacology MeSH
- bcl-2-Associated X Protein genetics metabolism MeSH
- Gene Expression Regulation, Neoplastic * MeSH
- Sphingolipids chemistry classification metabolism MeSH
- Signal Transduction MeSH
- Endoplasmic Reticulum Stress drug effects MeSH
- Drug Synergism MeSH
- Transcription Factor CHOP genetics metabolism MeSH
- X-Linked Inhibitor of Apoptosis Protein genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- BAK1 protein, human MeSH Browser
- BAX protein, human MeSH Browser
- Cytochromes c MeSH
- DDIT3 protein, human MeSH Browser
- EIF2AK3 protein, human MeSH Browser
- Inhibitor of Apoptosis Proteins MeSH
- eIF-2 Kinase MeSH
- Docosahexaenoic Acids MeSH
- bcl-2 Homologous Antagonist-Killer Protein MeSH
- TNF-Related Apoptosis-Inducing Ligand MeSH
- bcl-2-Associated X Protein MeSH
- Sphingolipids MeSH
- TNFSF10 protein, human MeSH Browser
- Transcription Factor CHOP MeSH
- X-Linked Inhibitor of Apoptosis Protein MeSH
- XIAP protein, human MeSH Browser
Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid present in fish oil, may exert cytotoxic and/or cytostatic effects on colon cancer cells when applied individually or in combination with some anticancer drugs. Here we demonstrate a selective ability of subtoxic doses of DHA to enhance antiproliferative and apoptotic effects of clinically useful cytokine TRAIL (tumor necrosis factor-related apoptosis inducing ligand) in cancer but not normal human colon cells. DHA-mediated stimulation of TRAIL-induced apoptosis was associated with extensive engagement of mitochondrial pathway (Bax/Bak activation, drop of mitochondrial membrane potential, cytochrome c release), activation of endoplasmic reticulum stress response (CHOP upregulation, changes in PERK level), decrease of cellular inhibitor of apoptosis protein (XIAP, cIAP1) levels and significant changes in sphingolipid metabolism (intracellular levels of ceramides, hexosyl ceramides, sphingomyelines, sphingosines; HPLC/MS/MS). Interestingly, we found significant differences in representation of various classes of ceramides (especially C16:0, C24:1) between the cancer and normal colon cells treated with DHA and TRAIL, and suggested their potential role in the regulation of the cell response to the drug combination. These study outcomes highlight the potential of DHA for a new combination therapy with TRAIL for selective elimination of colon cancer cells via simultaneous targeting of multiple steps in apoptotic pathways.
References provided by Crossref.org
Colon Cancer and Perturbations of the Sphingolipid Metabolism
