Genistein enhances the effect of trichostatin A on inhibition of A549 cell growth by increasing expression of TNF receptor-1

• Published in: Toxicology and applied pharmacology Vol. 262; no. 3; pp. 247 - 254
• Main Authors: Wu, Tzu-Chin, Yang, Ying-Chihi, Huang, Pei-Ru, Wen, Yu-Der, Yeh, Shu-Lan
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.08.2012; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; A549 cells; APOPTOSIS; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Caspases - metabolism; Cell Line, Tumor; DMSO; Dose-Response Relationship, Drug; Drug Synergism; ESTROGENS; Genistein; Genistein - pharmacology; Humans; Hydroxamic Acids - pharmacology; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; LUNGS; Medical sciences; MESSENGER-RNA; NEOPLASMS; POLYMERASE CHAIN REACTION; RECEPTORS; Receptors, Tumor Necrosis Factor, Type I - agonists; Receptors, Tumor Necrosis Factor, Type I - biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - metabolism; TNF receptor-1; Toxicology; TRANSCRIPTION; Trichostatin A; Up-Regulation - drug effects; TSA; A549 cells; DMSO; RT-PCR; Genistein; TNFR-1; siRNA; Trichostatin A; TNF receptor-1; Human; Cell proliferation; Tyrosine kinase inhibitor; Lung; Respiratory system; Isoflavone derivatives; Flavonoid; In vitro; Phytoestrogen; Polyphenol; Cell line; Tumor necrosis factor receptor; Phenols; Inhibition
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2012.05.003

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 (50ng/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 10μM 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 10μM 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. ► TSA combined with genistein rather than TSA alone increases the expression of TNFR-1. ► Genistein may exert such an effect partly through estrogen receptor pathway. ► The combined treatment increases the activation of caspase-10 and caspase-3. ► The combined treatment also increases the expression of p53 protein. ► TNFR-1 siRNA transfection suppresses the enhancing effect of genistein.