DHA-mediated enhancement of TRAIL-induced apoptosis in colon cancer cells is associated with engagement of mitochondria and specific alterations in sphingolipid metabolism.

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Authors	SKENDER Belma HOFMANOVÁ Jiřina SLAVÍK Josef JELÍNKOVÁ Iva MACHALA Miroslav MOYER Marry Pat KOZUBÍK Alois HYRŠLOVÁ VACULOVÁ Alena
Year of publication	2014
Type	Article in Periodical
Magazine / Source	Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
MU Faculty or unit	Faculty of Science
Citation
Web	https://www.sciencedirect.com/science/article/pii/S1388198114001164?via%3Dihub
Doi	http://dx.doi.org/10.1016/j.bbalip.2014.06.005
Field	Physiology
Keywords	Docosahexaenoic acid; TRAIL; Apoptosis; Lipid metabolism; Colon cancer
Description	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.
Related projects:	Podpora výzkumné činnosti studentů v oblasti fyziologie a imunologie živočichů v roce 2014.