DHA induces ER stress and growth arrest in human colon cancer cells: associations with cholesterol and calcium homeostasis

Polyunsaturated fatty acids (PUFAs) are normal constituents of the diet, but have properties different from other fatty acids (e.g., through generation of signaling molecules). N-3 PUFAs reduce cancer cell growth, but no unified mechanism has been identified. We show that docosahexaenoic acid (DHA;...

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Bibliographic Details
Published in:Journal of lipid research 2008-10, Vol.49 (10), p.2089-2100
Main Authors: Jakobsen, Caroline Hild, Størvold, Gro Leite, Bremseth, Hilde, Follestad, Turid, Sand, Kristin, Mack, Merete, Olsen, Karina Standahl, Lundemo, Anne Gøril, Iversen, Jens Gustav, Krokan, Hans Einar, Schønberg, Svanhild Arentz
Format: Article
Language:English
Subjects:
Antioxidants - metabolism
Apoptosis - drug effects
Apoptosis - genetics
Calcium - metabolism
Cell Line, Tumor
Cell Proliferation - drug effects
Cholesterol - metabolism
Colonic Neoplasms - genetics
Colonic Neoplasms - metabolism
Colonic Neoplasms - pathology
Cytosol - drug effects
Cytosol - metabolism
Docosahexaenoic Acids - pharmacology
Endoplasmic Reticulum - drug effects
Endoplasmic Reticulum - metabolism
Endoplasmic Reticulum - pathology
Gene Expression Regulation - drug effects
Homeostasis - drug effects
Humans
RNA, Messenger - genetics
RNA, Messenger - metabolism
Signal Transduction - drug effects
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Summary:Polyunsaturated fatty acids (PUFAs) are normal constituents of the diet, but have properties different from other fatty acids (e.g., through generation of signaling molecules). N-3 PUFAs reduce cancer cell growth, but no unified mechanism has been identified. We show that docosahexaenoic acid (DHA; 22:6 n-3) causes extensive changes in gene expression patterns at mRNA level in the colon cancer cell line SW620. Early changes include unfolded protein response (UPR) and increased levels of phosphorylated eIF2α as verified at protein level. The latter is considered a hallmark of endoplasmic reticulum (ER) stress and is abundantly present already after 3 h. It may coordinate many of the downstream changes observed, including signaling pathways for cell cycle arrest/apoptosis, calcium homeostasis, cholesterol metabolism, ubiquitination, and proteasomal degradation. Also, eicosapentaenoic acid (EPA), but not oleic acid (OA), induced key mediators of ER stress and UPR at protein level. Accumulation of esterified cholesterol was not compensated for by increased total levels of cholesterol, and mRNAs for cholesterol biosynthesis as well as de novo synthesis of cholesterol were reduced. These results suggest that cytotoxic effects of DHA are associated with signaling pathways involving lipid metabolism and ER stress.
ISSN:0022-2275
1539-7262
DOI:10.1194/jlr.M700389-JLR200