title: Copper depletion inhibits CoCl2-induced aggressive phenotype of MCF-7 cells via downregulation of HIF-1 and inhibition of Snail/Twist-mediated epithelial-mesenchymal transition.
abstract: Copper, a strictly regulated trace element, is essential for many physiological processes including angiogenesis. Dysregulated angiogenesis has been associated with increased copper in tumors, and thus copper chelators have been used to inhibit tumor angiogenesis. However, it remains unclear whether copper has any effect on epithelial-mesenchymal transition (EMT). Using CoCl2-induced EMT of human breast carcinoma MCF-7 cells, we found that TEPA, a copper chelator, inhibited EMT-like cell morphology and cytoskeleton arrangement triggered by CoCl2; decreased the expression of vimentin and fibronectin, markers typical of EMT; inhibited HIF-1 activation and HIF1-α accumulation in nuclear; and down-regulated the expression of hypoxia-associated transcription factors, Snail and Twist1. Moreover, knockdown copper transport protein, Ctr1, also inhibited CoCl2-induced EMT and reversed the mesenchymal phenotype. In EMT6 xenograft mouse models, TEPA administration inhibited the tumor growth and increased mice survival. Immunohistochemical analysis of the xenograft further demonstrated that TEPA administration significantly inhibited tumor angiogenesis, down-regulated hypoxia-induced transcription factors, Snail and Twist1, leading to decreased transactivation of EMT-associated marker genes, vimentin and fibronectin. These results indicate that TEPA inhibits CoCl2-induced EMT most likely via HIF1-α-Snail/Twist signaling pathway, and copper depletion may be exploited as a therapeutic for breast cancer.
authors.affiliation: Department of Biophysics, School of Life Science and Technology.
authors.forename: Shun
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biophysics, School of Life Science and Technology.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 1] Department of Biophysics, School of Life Science and Technology [2] Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: 1] Department of Biophysics, School of Life Science and Technology [2] Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Wu
authors.affiliation: Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, CA 92103, USA.
authors.forename: Xitong
authors.initials: X
authors.lastname: Dang
authors.affiliation: 1] Department of Biophysics, School of Life Science and Technology [2] Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, P.R. China.
authors.forename: Yiyao
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016764:Cell Polarity; D003035:Cobalt / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000378:metabolism*; D000079923:Copper Transporter 1; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous; D013721:Triethylenephosphoramide / Q000627:therapeutic use / Q000633:toxicity; D051879:Twist-Related Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D005353:Fibronectins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C490079:SLC31A1 protein, human; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D014746:Vimentin; D003035:Cobalt; D003300:Copper; C018021:cobaltous chloride; D013721:Triethylenephosphoramide