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Papers In Press, published online ahead of print October 1, 2008
J. Lipid Res., doi:10.1194/jlr.M700389-JLR200

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Journal of Lipid Research, Vol. 49, 2089-2100, October 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

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

Caroline Hild Jakobsen^1,*, Gro Leite Størvold^1,*,, Hilde Bremseth^1,, Turid Follestad, Kristin Sand^**, Merete Mack^*, Karina Standahl Olsen, Anne Gøril Lundemo^*, Jens Gustav Iversen^2,**, Hans Einar Krokan and Svanhild Arentz Schønberg^3,*

^* Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Erling Skjalgssons gate 1, N-7006 Trondheim, Norway
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Erling Skjalgssons gate 1, N-7006 Trondheim, Norway
Department of Mathematical Sciences, Norwegian University of Science and Technology (NTNU), Erling Skjalgssons gate 1, N-7006 Trondheim, Norway
^** Institute of Basic Medical Sciences, Department of Physiology, Domus Medica, University of Oslo, Gaustad, Sognsvannsveien 9, 0372 Oslo, Norway
Department of Medical Genetics, Ullevål University Hospital, Faculty of Medicine, University of Oslo, 0318 Oslo, Norway

^* The project was financed by The Faculty of Medicine, NTNU, The Cancer Research Fund, Trondheim University Hospital, and The Research Council of Norway through grants from the Functional Genomics Program (FUGE). Microarray experiments were performed at the microarray core facility at the Norwegian Microarray Consortium (NMC), Trondheim, which is supported by FUGE, The Norwegian Research Council. Financial support was also given by the cross-disciplinary project "BIOEMIT-Prediction and modification in functional genomics: combining bioinformatical, bioethical, biomedical, and biotechnological research," NTNU.

The online version of this article (available at http://www.jlr.org) contains supplementary data.

Published, JLR Papers in Press, June 19, 2008.

¹ C. H. Jakobsen, G. L. Størvold, and H. Bremseth contributed equally to this work.

² Deceased.

³ To whom correspondence should be addressed. e-mail: svanhild.schonberg{at}ntnu.no

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 eIF2 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.

Supplementary key words gene expression • phosphorylated eIF2 • antioxidant response • heat shock response • cytosolic free Ca²⁺ • cell cycle • total cholesterol level • cholesterol synthesis

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