Omega-3 polyunsaturated fatty acids down-modulate CXCR4 expression and function in MDA-MB-231 breast cancer cells.
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. Much is known of the beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) on cancer; however, the mechanisms behind these effects are unclear. For this study, we investigated the effects of two n-3 PUFAs, docosahexaenoic acid and eicosapentaenoic acid, on CXCR4 expression and activity in the MDA-MB-231 breast cancer cell line. We compared the n-3 PUFAs with the saturated fatty acid stearic acid as a control. Treatment of the cells with n-3 PUFAs resulted in reduced surface expression of CXCR4, but had no effect on overall CXCR4 expression. Consequently, we found that the fatty acid treatment significantly reduced CXCR4-mediated cell migration. Successful CXCR4-mediated signaling and migration requires the cholesterol-rich membrane microdomains known as lipid rafts. Treatment with n-3 PUFAs disrupted the lipid raft domains in a manner similar to methyl-beta-cyclodextrin and resulted in a partial displacement of CXCR4, suggesting a possible mechanism behind the reduced CXCR4 activity. These results were not observed in cells treated with stearic acid. Together, our data suggest that n-3 PUFAs may have a preventative effect on breast cancer metastasis in vitro. This suggests a previously unreported potential benefit of n-3 PUFAs to patients with metastatic breast cancer. The data presented in this study may also translate to other disorders that involve up-regulated chemokine receptors.
Altenburg
Jeffrey D
JD
Cellular Biochemistry Laboratory, Methodist Research Institute, Clarian Health Partners, Indianapolis, IN 46202, USA.
Siddiqui
Rafat A
RA
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D051242:Caveolin 1; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid