Induction of apoptosis by Trichostatin A in human breast cancer cell lines: involvement of 15-Lox-1.
15-Lipoxygenase-1 (15-Lox-1) is a key enzyme mediating oxidative metabolism of polyunsaturated fatty acids and has attracted considerable interest as a potential target for the induction of apoptosis in cancer cells. Knowledge of relationship between 15-Lox-1 and histone deacetylase inhibitors is lacking in the breast cancer. This study is aimed to investigate the role of Trichostatin A (TSA) and 13(S)-HODE, as a metabolite of 15-Lox-1, in the regulation of breast cancer cell growth. The cytotoxic effect of TSA, as a potent HDAC inhibitor, was measured using MTT assay. Annexin V-FITC and PI staining were performed to detect apoptosis and cell cycle distribution using Flow cytometry. The role of 15-Lox-1 in the regulation of cell growth was assessed by 15-Lox-1 inhibitor and the level of 15-Lox-1 metabolite was measured to determine 15-Lox activity after treatment by TSA. The results demonstrated that TSA induced cell growth inhibition via 15-Lox-1, in a dose- and time-dependent manner, and subsequently accompanied by the cell cycle arrest and induction of apoptosis. Moreover, growth inhibitory effect of TSA was associated with the elevation of 15-Lox-1 metabolite (13(S)-HODE). This study provided evidences that the inhibitory effect of TSA on the breast cancer cell growth occurs via the induction of 15-Lox-1 activity and 13(S)-HODE production. Our findings underline the possible role of 15-Lox-1/13(S)-HODE pathway as a promising molecular approach for the induction of apoptosis in breast cancer cells.
Cancer Research Laboratory, Department of Clinical Biochemistry, School of Medical Sciences, Tarbiat Modares University, P.O. Box 14115-331, Tehran, Iran.
Masoumeh
M
Tavakoli-Yaraki
Fatemeh
F
Karami-Tehrani
Vahid
V
Salimi
Majid
M
Sirati-Sabet
D017209:Apoptosis; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008041:Linoleic Acids / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008041:Linoleic Acids; D016859:Lipoxygenase Inhibitors; C012589:trichostatin A; C024348:13-hydroxy-9,11-octadecadienoic acid; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase