Omega-3 Polyunsaturated Fatty Acids Down-Modulate CXCR4 Expression and Function in MDA-MB-231 Breast Cancer Cells

Altenburg, Jeffrey D.; Siddiqui, Rafat A.

doi:10.1158/1541-7786.mcr-08-0385

Cited by 59 publications

(43 citation statements)

References 46 publications

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“…Our data suggest DHA could prevent recruitment of the protein into lipid rafts from nonrafts as a consequence of the disruption in the spatial distribution of rafts (which may be occurring on several length scales). As another example, it was proposed that suppression of MDA-MB-231 breast cancer migration with (n-3) PUFA was due to an inability of the chemokine receptor CXCR4 to cluster, but the mechanism was not investigated (50). We propose a disruption in lipid rafts could prevent CXCR4 clustering and one approach would be to measure CXCR4 clustering with FRET imaging on a nanometer scale.…”

Section: Discussionmentioning

confidence: 96%

Membrane Raft Organization Is More Sensitive to Disruption by (n-3) PUFA Than Nonraft Organization in EL4 and B Cells

Rockett

Franklin

Harris

et al. 2011

The Journal of Nutrition

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Model membrane and cellular detergent extraction studies show (n-3) PUFA predominately incorporate into nonrafts; thus, we hypothesized (n-3) PUFA could disrupt nonraft organization. The first objective of this study was to determine whether (n-3) PUFA disrupted nonrafts of EL4 cells, an extension of our previous work in which we discovered an (n-3) PUFA diminished raft clustering. EPA or DHA treatment of EL4 cells increased plasma membrane accumulation of the nonraft probe 1,1'-dilinoleyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate by ~50-70% relative to a BSA control. Förster resonance energy transfer imaging showed EPA and DHA also disrupted EL4 nanometer scale nonraft organization by increasing the distance between nonraft molecules by ~25% compared with BSA. However, changes in nonrafts were due to an increase in cell size; under conditions where EPA or DHA did not increase cell size, nonraft organization was unaffected. We next translated findings on EL4 cells by testing if (n-3) PUFA administered to mice disrupted nonrafts and rafts. Imaging of B cells isolated from mice fed low- or high-fat (HF) (n-3) PUFA diets showed no change in nonraft organization compared with a control diet (CD). However, confocal microscopy revealed the HF (n-3) PUFA diet disrupted lipid raft clustering and size by ~40% relative to CD. Taken together, our data from 2 different model systems suggest (n-3) PUFA have limited effects on nonrafts. The ex vivo data, which confirm previous studies with EL4 cells, provide evidence that (n-3) PUFA consumed through the diet disrupt B cell lipid raft clustering.

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Section: Discussionmentioning

confidence: 96%

Membrane Raft Organization Is More Sensitive to Disruption by (n-3) PUFA Than Nonraft Organization in EL4 and B Cells

Rockett

Franklin

Harris

et al. 2011

The Journal of Nutrition

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“…Another well-known therapeutic target for BC metastasis is the chemokine receptor, CXCR4. Treatment of BC cells with DHA or EPA caused redistribution of CXCR4 from lipid rafts to the cell surface [105], resulting in an overall reduction in cell migration. In addition to shifting proteins out of lipid rafts, n -3 PUFA can prompt the localization of some proteins into these domains.…”

Section: N-3 Pufa Lipid Rafts and Breast Cancermentioning

confidence: 99%

n-3 Polyunsaturated Fatty Acids and Mechanisms to Mitigate Inflammatory Paracrine Signaling in Obesity-Associated Breast Cancer

et al. 2014

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Globally, the prevalence of obesity is increasing which subsequently increases the risk of the development of obesity-related chronic diseases. Low-grade chronic inflammation and dysregulated adipose tissue inflammatory mediator/adipokine secretion are well-established in obesity, and these factors increase the risk of developing inflammation-associated cancer. Breast cancer is of particular interest given that increased inflammation within the subcutaneous mammary adipose tissue depot can alter the local tissue inflammatory microenvironment such that it resembles that of obese visceral adipose tissue. Therefore, in obese women with breast cancer, increased inflammatory mediators both locally and systemically can perpetuate inflammation-associated pro-carcinogenic signaling pathways, thereby increasing disease severity. Herein, we discuss some of these inflammation-associated pro-carcinogenic mechanisms of the combined obese breast cancer phenotype and offer evidence that dietary long chain n-3 polyunsaturated fatty acids (PUFA) may have utility in mitigating the severity of obesity-associated inflammation and breast cancer.

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“…ω−3 PUFAs also decreased the activity of the oncogenes ras and AP-1 downstream from the EGFR, which inhibited mitosis (Hardman, 2002). It has also been shown that ω−3 PUFA decrease membrane expression of the chemokine receptor CXCR4 in MDA-MB-231 breast cancer cells, which decreases their migration potential (Altenburg & Siddiqui, 2009). This appears to be due to the incorporation of ω−3 PUFAs into the cell membrane, which disrupts the cholesterol-rich lipid rafts that are required for CXCR4 dimerization and signaling through NF-κB (Wang et al, 2006).…”

Section: Anticancer Mechanisms Of ω−3 Pufasmentioning

confidence: 97%

Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs

Murray

Hraiki

Bebawy

et al. 2015

Pharmacology & Therapeutics

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Lipids have the potential for development as anticancer agents. Endogenous membrane lipids, such as ceramides and certain saturated fatty acids, have been found to modulate the viability of tumor cells. In addition, many tumors over-express cyclooxygenase, lipoxygenase or cytochrome P450 enzymes that mediate the biotransformation of ω-6 polyunsaturated fatty acids (PUFAs) to potent eicosanoid regulators of tumor cell proliferation and cell death. In contrast, several analogous products from the biotransformation of ω-3 PUFAs impair particular tumorigenic pathways. For example, the ω-3 17,18-epoxide of eicosapentaenoic acid activates anti-proliferative and proapoptotic signaling cascades in tumor cells and the lipoxygenase-derived resolvins are effective inhibitors of inflammatory pathways that may drive tumor expansion. However, the development of potential anti-cancer drugs based on these molecules is complex, with in vivo stability a major issue. Nevertheless, recent successes with the antitumor alkyl phospholipids, which are synthetic analogues of naturally-occurring membrane phospholipid esters, have provided the impetus for development of further molecules. The alkyl phospholipids have been tested against a range of cancers and show considerable activity against skin cancers and certain leukemias. Very recently, it has been shown that combination strategies, in which alkyl phospholipids are used in conjunction with established anticancer agents, are promising new therapeutic approaches. In future, the evaluation of new lipid-based molecules in single-agent and combination treatments may also be assessed. This could provide a range of important treatment options in the management of advanced and metastatic cancer.

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Omega-3 Polyunsaturated Fatty Acids Down-Modulate CXCR4 Expression and Function in MDA-MB-231 Breast Cancer Cells

Abstract: Metastasis is the leading cause of death from breast cancer. A major factor of metastasis is the migration of cancerous cells to other tissues by way of up-regulated chemokine receptors, such as CXCR4, on the cell surface.

Cited by 59 publications

References 46 publications

Membrane Raft Organization Is More Sensitive to Disruption by (n-3) PUFA Than Nonraft Organization in EL4 and B Cells

Membrane Raft Organization Is More Sensitive to Disruption by (n-3) PUFA Than Nonraft Organization in EL4 and B Cells

n-3 Polyunsaturated Fatty Acids and Mechanisms to Mitigate Inflammatory Paracrine Signaling in Obesity-Associated Breast Cancer

Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs

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