title: Docosahexaenoic acid activates some SREBP-2 targets independent of cholesterol and ER stress in SW620 colon cancer cells.
abstract: The SREBP-2 transcription factor is mainly activated by low cellular cholesterol levels. However, other factors may also cause SREBP-2 activation. We have previously demonstrated activation of SREBP-2 by the polyunsaturated fatty acid docosahexaenoic acid (DHA) in SW620 colon cancer cells. Despite activation of SREBP-2, only a few target genes were induced and cholesterol biosynthesis was reduced. In the present study, gene expression analysis at early time points verified the previously observed SREBP-2 target gene expression pattern. Activation of SREBP-2 using siRNAs targeting Niemann Pick C1 protein (NPC1) led to increased expression of all SREBP target genes examined, indicating that activation of some SREBP-2 target genes is inhibited during DHA-treatment. Cholesterol supplementation during DHA treatment did not abolish SREBP-2 activation. We also demonstrate that activation of SREBP-2 is independent of ER stress and eIF2alpha phosphorylation, which we have previously observed in DHA-treated cells. Thapsigargin-induced ER stress repressed expression of SREBP-2 target genes, but with a different pattern than observed in DHA-treated cells. Moreover, oleic acid (OA) treatment, which does not induce ER stress in SW620 cells, led to activation of SREBP-2 and induced a target gene expression pattern similar to that of DHA-treated cells. These results indicate that DHA and OA may activate SREBP-2 and inhibit activation of SREBP-2 target genes through a mechanism independent of cholesterol level and ER stress.
authors: Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Erling Skjalgssons gate 1, Trondheim, Norway.
authors: Gro Leite
authors: GL
authors: Størvold
authors: Karianne Giller
authors: KG
authors: Fleten
authors: Cathrine Goberg
authors: CG
authors: Olsen
authors: Turid
authors: T
authors: Follestad
authors: Hans Einar
authors: HE
authors: Krokan
authors: Svanhild Arentz
authors: SA
authors: Schønberg
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019301:Oleic Acid / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000502:physiology*; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics
chemical_list: D012333:RNA, Messenger; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D004281:Docosahexaenoic Acids; D019301:Oleic Acid; D002784:Cholesterol