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

Belma Skender, Jiřina Hofmanová, Josef Slavík, Iva Jelínková, Miroslav Machala, Mary Pat Moyer, Alois Kozubík, Alena Hyrslova Vaculova

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1308-1317
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1841
Issue number9
DOIs
StatePublished - Sep 2014
Externally publishedYes

Keywords

  • Apoptosis
  • Colon cancer
  • Docosahexaenoic acid
  • Lipid metabolism
  • TRAIL

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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