Docosahexaenoic Acid Activates Some SREBP‐2 Targets Independent of Cholesterol and ER Stress in SW620 Colon Cancer Cells

Størvold, Gunnar; Fleten, Karianne G.; Olsen, Cathrine Goberg; Follestad, Turid; Krokan, Hans E.; Schønberg, Svanhild A.

doi:10.1007/s11745-009-3324-4

Cited by 11 publications

(10 citation statements)

References 56 publications

(122 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is unlikely however that ω3PUFAs interfere with this axis in HT29-dx cells: they indeed reduced HMGCoAR activity and protein in chemoresistant cells, but did not decrease the nuclear translocation of SREBP-2 and the transcription of HMGCoAR gene. Our data are partially in contrast with previous works showing that DHA activated SREBP-2 in SW620 colon cancer cells [23,24], without changing however the transcription of HMGCoAR [23]. As far as we know, these works were performed on colon cancer cells without a MDR phenotype; this may explain the different behavior of DHA in SW620 cells and in chemoresistant HT29-dx cells.…”

Section: Discussioncontrasting

confidence: 99%

“…To our knowledge, this is the first work reporting that ω3PUFAs activate the E3 ligase Trc8. This observation also provides mechanistic insights to explain previous works, reporting that DHA increases the activity of ERAD system [23,24], and the proteasomal degradation of specific proteins in colon cancer [50]. Contrarily to DHA and EPA, AA had no effect on Trc8, in keeping with its inefficacy in reducing HMGCoAR and cholesterol synthesis.…”

Section: Discussionsupporting

confidence: 77%

“…In colon cancer cells, the effects of ω3PUFAs are more controversial: for instance, EPA inhibits HMGCoAR activity in CaCo-2 colon cancer cells [22]; DHA has little effect on the de novo synthesis of cholesterol in SW620 cells [23], although it increases the sterol regulatory element binding protein-2 (SREBP-2), which induces the transcription of several genes involved in the cholesterol synthesis - e.g. HMGCoAR and 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMGCoAS) [23,24]. …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition

et al. 2013

View full text Add to dashboard Cite

BackgroundThe activity of P-glycoprotein (Pgp) and multidrug resistance related protein 1 (MRP1), two membrane transporters involved in multidrug resistance of colon cancer, is increased by high amounts of cholesterol in plasma membrane and detergent resistant membranes (DRMs). It has never been investigated whether omega 3 polyunsatured fatty acids (PUFAs), which modulate cholesterol homeostasis in dyslipidemic syndromes and have chemopreventive effects in colon cancer, may affect the response to chemotherapy in multidrug resistant (MDR) tumors.MethodsWe studied the effect of omega 3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in human chemosensitive colon cancer HT29 cells and in their MDR counterpart, HT29-dx cells.ResultsMDR cells, which overexpressed Pgp and MRP1, had a dysregulated cholesterol metabolism, due to the lower expression of ubiquitin E3 ligase Trc8: this produced lower ubiquitination rate of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCoAR), higher cholesterol synthesis, higher cholesterol content in MDR cells. We found that DHA and EPA re-activated Trc8 E3 ligase in MDR cells, restored the ubiquitination rate of HMGCoAR to levels comparable with chemosensitive cells, reduced the cholesterol synthesis and incorporation in DRMs. Omega 3 PUFAs were incorporated in whole lipids as well as in DRMs of MDR cells, and altered the lipid composition of these compartments. They reduced the amount of Pgp and MRP1 contained in DRMs, decreased the transporters activity, restored the antitumor effects of different chemotherapeutic drugs, restored a proper tumor-immune system recognition in response to chemotherapy in MDR cells.ConclusionsOur work describes a new biochemical effect of omega 3 PUFAs, which can be useful to overcome chemoresistance in MDR colon cancer cells.

show abstract

Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Similar to our results, preadipocytes and mesenchymal stem cells treated with saturated PAL demonstrated multiple ER stress responses, evident by increased splicing of Xbp-1 mRNA [27, , 42]. Exposure of human colon cancer cells (SW620) to DHA (70 mM) has been shown to induce ER stress, as demonstrated by increased levels of phosphorylated eIF2α and the ER-localized PERK pathway [43]. The mechanism by which PAL or DHA induce cellular stress is still not clear.…”

Section: Discussionsupporting

confidence: 81%

Exocrine pancreas ER stress is differentially induced by different fatty acids

Danino

Ben-Dror

Birk

2015

Experimental Cell Research

View full text Add to dashboard Cite

“…Saturated lipids have been shown to induce cholesterol biosynthesis ( 27 ), while lipids rich in polyunsaturated fatty acids have been shown to reduce cholesterol biosynthesis in the liver ( 28 ). Moreover, in vitro experiments have previously demonstrated that the polyunsaturated fatty acid, DHA, activates SREBP2 without increasing cholesterol biosynthesis ( 29,30 ), suggesting that polyunsaturated fatty acids regulate cholesterol biosynthesis through alternative mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism

Caesar

Nygrén

Orešič

et al. 2016

Journal of Lipid Research

View full text Add to dashboard Cite

This article is available online at http://www.jlr.org dyslipidemia, increased hepatic lipogenesis, and liver steatosis ( 1 ). In contrast, consumption of polyunsaturated fatty acids is associated with a lean and metabolically healthy phenotype ( 2-4 ). Emerging evidence suggests that some of the effects of dietary lipids on host metabolism may be mediated by modifi cations of the gut microbiota composition, which result in altered metabolic properties of the gut microbiota ( 5-8 ) and/or by alterations in gut integrity, which affect the extent of leakage of microbially derived metabolites into the circulation ( 6 ).Metabolites produced by the gut microbiota may be utilized as a source of energy by the host or may act as signaling molecules that infl uence host metabolism ( 8 ). These metabolites can have a local effect in the intestine, but may also be transferred from the gut into the circulation, thereby affecting peripheral tissues ( 8 ). Indeed, germfree (GF) mice have been shown to have improved glucose sensitivity and to be protected against obesity and dyslipidemia ( 9-12 ), exemplifying the systemic importance of the microbiota. Because of its proximity to the gastrointestinal tract, the liver is strongly affected by the microbiota, and bacterial status has been shown to affect both hepatic lipid biosynthesis ( 9 ) and lipid degradation ( 13 ). Several mechanisms linking bacterial metabolic processes with liver metabolism have been described ( 14 ); for example, microbial processing of dietary fi bers, bile acids, and choline produces metabolites that regulate the activity of hepatic transcription factors and, hence, metabolic processes.Abstract The gut microbiota infl uences many aspects of host metabolism. We have previously shown that the presence of a gut microbiota remodels lipid composition. Here we investigated how interaction between gut microbiota and dietary lipids regulates lipid composition in the liver and plasma, and gene expression in the liver. Germ-free and conventionally raised mice were fed a lard or fi sh oil diet for 11 weeks. We performed lipidomics analysis of the liver and serum and microarray analysis of the liver. As expected, most of the variation in the lipidomics dataset was induced by the diet, and abundance of most lipid classes differed between mice fed lard and fi sh oil. However, the gut microbiota also affected lipid composition. The gut microbiota increased hepatic levels of cholesterol and cholesteryl esters in mice fed lard, but not in mice fed fi sh oil. Serum levels of cholesterol and cholesteryl esters were not affected by the gut microbiota. Genes encoding enzymes involved in cholesterol biosynthesis were downregulated by the gut microbiota in mice fed lard and were expressed at a low level in mice fed fi sh oil independent of microbial status. In summary, we show that gut microbiota-induced regulation of hepatic cholesterol metabolism is dependent on dietary lipid composition. -Caesar, R., H. Nygren, M. Orešič, and F. The composition of dietary fat is known to ...

show abstract

Docosahexaenoic Acid Activates Some SREBP‐2 Targets Independent of Cholesterol and ER Stress in SW620 Colon Cancer Cells

Cited by 11 publications

References 56 publications

Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition

Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition

Exocrine pancreas ER stress is differentially induced by different fatty acids

Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism

Contact Info

Product

Resources

About