title: Regulation of colorectal cancer cell apoptosis by the n-3 polyunsaturated fatty acids Docosahexaenoic and Eicosapentaenoic.
abstract: Several studies have suggested that the n-3 fatty acids Docosahexaenoic (DHA) and Eicosapentaenoic (EPA) have an important protective effect on colorectal cancer, and this could be at least partly due to their proapoptotic activity. It is unclear, however, how this phenomenon is triggered and what mechanisms are implicated. Here, we show that both DHA and EPA have an important proapoptotic effect on colorectal cancer cells with different molecular phenotypes but not in noncancerous cells. Apoptosis is caspase dependent, and both intrinsic and extrinsic pathways are implicated. The dimerization of Bax and Bak, the depolarization of the mitochondrial membrane, and the subsequent release of cytochrome c and Smac/Diablo to the cytosol evidence the activation of the intrinsic pathway. The implication of the extrinsic pathway is shown by the activation of caspase-8, along with the down-regulation of FLIP. The timing of caspase-8 activation, and the oligomerization of Bid with Bax, suggest a cross-talk with the intrinsic pathway. None of the death receptors that commonly initiate the extrinsic pathway: FAS, TNF-R1, and TRAIL-R2 are found to be responsible for triggering the apoptosis cascade induced by DHA and EPA. Neither PPARgamma nor cyclooxygenase-2, two likely candidates to regulate this process, play a significant role. Our findings suggest that the down-regulation of two key regulatory elements of the extrinsic and intrinsic pathways, FLIP and XIAP, respectively, is determinant in the induction of apoptosis by DHA and EPA. These fatty acids could potentially be useful adjuvant anticancer agents in combination with other chemotherapeutic elements.
authors.affiliation: Department of Medicine, University of Illinois at Chicago, 840 South Wood Street (M/C 716), Chicago, IL 60612, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Giros
authors.forename: Mike
authors.initials: M
authors.lastname: Grzybowski
authors.forename: Vanessa R
authors.initials: VR
authors.lastname: Sohn
authors.forename: Elisenda
authors.initials: E
authors.lastname: Pons
authors.forename: Jessica
authors.initials: J
authors.lastname: Fernandez-Morales
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Xicola
authors.forename: Puja
authors.initials: P
authors.lastname: Sethi
authors.forename: Jessica
authors.initials: J
authors.lastname: Grzybowski
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
authors.forename: Miquel A
authors.initials: MA
authors.lastname: Gassull
authors.forename: Xavier
authors.initials: X
authors.lastname: Llor
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D020169:Caspases / Q000378:metabolism / Q000502:physiology; D015179:Colorectal Neoplasms / Q000473:pathology*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000473:pathology; D055503:Protein Multimerization / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D015525:Fatty Acids, Omega-3; D051028:bcl-2-Associated X Protein; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D020169:Caspases