Five-lipoxygenase inhibitors can mediate apoptosis in human breast cancer cell lines through complex eicosanoid interactions.
Many arachidonic acid metabolites function in growth signaling for epithelial cells, and we previously reported the expression of the major arachidonic acid enzymes in human breast cancer cell lines. To evaluate the role of the 5-lipoxygenase (5-LO) pathway on breast cancer growth regulation, we exposed cells to insulinlike growth factor-1 or transferrin, which increased the levels of the 5-LO metabolite, 5(S)-hydrooxyeicosa-6E,8C,11Z,14Z-tetraenoic acid (5-HETE), by radioimmunoassay and high-performance liquid chromatography. Addition of 5-HETE to breast cancer cells resulted in growth stimulation, whereas selective biochemical inhibitors of 5-LO reduced the levels of 5-HETE and related metabolites. Application of 5-LO or 5-LO activating protein-directed inhibitors, but not a cyclooxygenase inhibitor, reduced growth, increased apoptosis, down-regulated bcl-2, up-regulated bax, and increased G1 arrest. Exposure of breast cancer cells to a 5-LO inhibitor up-regulated peroxisome proliferator-activated receptor (PPAR)a and PPARg expression, and these same cells were growth inhibited when exposed to relevant PPAR agonists. These results suggest that disruption of the 5-LO signaling pathway mediates growth arrest and apoptosis in breast cancer cells. Additional experiments suggest that this involves the interplay of several factors, including the loss of growth stimulation by 5-LO products, the induction of PPARg, and the potential activation of PPARg by interactions with shunted endoperoxides.
Avis
I
I
Intervention Section, Department of Cell and Cancer Biology, Division of Clinical Sciences, National Cancer Institute, NIH Clinical Center, 9000 Rockville Pike, Bethesda, MD 20892-1906, USA.
Hong
S H
SH
Martinez
A
A
Moody
T
T
Choi
Y H
YH
Trepel
J
J
Das
R
R
Jett
M
M
Mulshine
J L
JL
D017209:Apoptosis; D016718:Arachidonic Acid / Q000378:metabolism*; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects; D015777:Eicosanoids / Q000378:metabolism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism* / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008024:Ligands; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein; D002722:Chlorobenzenes
D016718:Arachidonic Acid; D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; D007211:Indoles; D007334:Insulin-Like Growth Factor I; D008024:Ligands; D016859:Lipoxygenase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C060893:MK-886; D002722:Chlorobenzenes; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid