title: Genistein enhances the effect of trichostatin A on inhibition of A549 cell growth by increasing expression of TNF receptor-1.
abstract: Our previous study has shown that genistein enhances apoptosis in A549 lung cancer cells induced by trichostatin A (TSA). The precise molecular mechanism underlying the effect of genistein, however, remains unclear. In the present study, we investigated whether genistein enhances the anti-cancer effect of TSA through up-regulation of TNF receptor-1 (TNFR-1) death receptor signaling. We incubated A549 cells with TSA (50 ng/mL) alone or in combination with genistein and then determined the mRNA and protein expression of TNFR-1 as well as the activation of downstream caspases. Genistein at 5 and 10 μM significantly enhanced the TSA-induced decrease in cell number and apoptosis in a dose-dependent manner. The combined treatment significantly increased mRNA and protein expression of TNFR-1 at 6 and 12h, respectively, compared with that of the control group; while TSA alone had no effect. TSA in combination with 10 μM of genistein increased TNFR-1 mRNA and protein expression by about 70% and 40%, respectively. The underlying mechanism for this effect of genistein may be partly associated with the estrogen receptor pathway. The combined treatment also increased the activation of caspase-3 and -10 as well as p53 protein expression in A549 cells. The enhancing effects of genistein on the TSA-induced decrease in cell number and on the expression of caspase-3 in A549 cells were suppressed by silencing TNFR-1 expression. These data demonstrated that the upregulation of TNFR-1 death receptor signaling plays an important role, at least in part, in the enhancing effect of genistein on TSA-induced apoptosis in A549 cells.
authors.affiliation: Chest Clinic, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC.
authors.forename: Tzu-Chin
authors.initials: TC
authors.lastname: Wu
authors.forename: Ying-Chihi
authors.initials: YC
authors.lastname: Yang
authors.forename: Pei-Ru
authors.initials: PR
authors.lastname: Huang
authors.forename: Yu-Der
authors.initials: YD
authors.lastname: Wen
authors.forename: Shu-Lan
authors.initials: SL
authors.lastname: Yeh
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000819:agonists* / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; C012589:trichostatin A; D019833:Genistein; D020169:Caspases