title: Methylseleninic acid (MSA) inhibits 17β-estradiol-induced cell growth in breast cancer T47D cells via enhancement of the antioxidative thioredoxin/ thioredoxin reductase system.
abstract: The purpose of this study was to clarify the cell growth inhibitory mechanism of human breast cancer cells caused by selenium (Se) compounds. In the presence of 17β-estradiol (E(2)) at physiological concentrations, growth of estrogen receptor α (ERα)-positive T47D cells was markedly inhibited by 1 × 10(-6) mol/L methylseleninic acid (MSA) with no Se related toxicity.Under conditions where cell growth was inhibited, MSA decreased ERα mRNA levels and subsequent protein levels; further decreasing expression of estrogen-responsive finger protein (Efp) which is a target gene product of ERα and promotes G2/M progression of the cell cycle. Therefore, the decline in Efp expression is presumed to be involved in G2 arrest. Coincidentally, the antioxidative thioredoxin/ thioredoxin reductase (Trx/TrxR) system in cells was enhanced by the synergistic action of E(2) and MSA. It has been reported that ROS-induced oxidative stress enhanced ERα expression. E(2) increased production of intracellular ROS in T47D cells. Meanwhile, MSA significantly decreased E(2)-induced ROS accumulation. From these results, activation of the Trx/TrxR system induced by the coexistence of MSA and E(2) suppresses oxidative stress and decreases expression of ERα, and finally induces the growth arrest of T47D cells through disruption of ERα signaling.
authors.affiliation: Department of Public Health & Preventive Pharmacology, Setsunan University, Nagaotogecho, Hirakata, Osaka, Japan. okuno@pharm.setsunan.ac.jp
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Okuno
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Miura
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Sakazaki
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nakamuro
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ueno
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004357:Drug Synergism; D004789:Enzyme Activation; D004958:Estradiol / Q000009:adverse effects*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016566:Organoselenium Compounds / Q000494:pharmacology*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D016566:Organoselenium Compounds; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C491203:TXN protein, human; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D004958:Estradiol; D013879:Thioredoxins; C008493:methylselenic acid; D005979:Glutathione Peroxidase; D013880:Thioredoxin-Disulfide Reductase; C084523:TRIM25 protein, human; D044767:Ubiquitin-Protein Ligases; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human