Docosahexaenoic acid activates some SREBP-2 targets independent of cholesterol and ER stress in SW620 colon cancer cells.
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.
Størvold
Gro Leite
GL
Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Erling Skjalgssons gate 1, Trondheim, Norway.
Fleten
Karianne Giller
KG
Olsen
Cathrine Goberg
CG
Follestad
Turid
T
Krokan
Hans Einar
HE
Schønberg
Svanhild Arentz
SA
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
D012333:RNA, Messenger; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D004281:Docosahexaenoic Acids; D019301:Oleic Acid; D002784:Cholesterol