The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer cells.
Previous experimental studies have shown that high dietary fat intake is associated with mammary carcinogenesis. In the current study, the effect of 5-LOX or 12-LOX inhibitors on human breast cancer cell proliferation and apoptosis, as well as the possible mechanisms were investigated. The LOX inhibitors, NDGA, Rev-5901, and baicalein all inhibited proliferation and induced apoptosis in MCF-7 (ER+) and MDA-MB-231 (ER-) breast cancer cell in vitro. In contrast, the LOX products, 5-HETE and 12-HETE had mitogenic effects, stimulating the proliferation of both cell lines. These inhibitors also induced cytochrome c release, caspase-9 activation, as well as downstream caspase-3, caspase-7 activation, and PARP cleavage. LOX inhibitor treatment also reduced the levels of anti-apoptotic proteins Bcl-2 and Mcl-1 and increased the levels of the pro-apoptotic protein bax. In conclusion, blockade of both 5-LOX and 12-LOX pathways induces apoptosis in breast cancer cells through the cytochrome c release and caspase-9 activation, with changes in the levels of Bcl-2 family proteins.
Department of Surgery, Gastrointestinal Oncology Laboratories, Northwestern University Medical School, Chicago, IL 60611, USA.
Wei-Gang
WG
Tong
Xian-Zhong
XZ
Ding
Thomas E
TE
Adrian
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D053148:Caspase 3; D053179:Caspase 7; D053453:Caspase 9; D020169:Caspases / Q000096:biosynthesis / Q000378:metabolism; D002455:Cell Division; D002630:Chemotactic Factors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008934:Mitogens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D002630:Chemotactic Factors; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D008934:Mitogens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053179:Caspase 7; D053453:Caspase 9; D020169:Caspases