title: Elevation of cysteine consumption in tamoxifen-resistant MCF-7 cells.
abstract: Tamoxifen (TAM) resistance is a main cause of therapeutic failure in breast cancers. Although methionine dependency is a phenotypic characteristic of tumor cells, the role of sulfur amino acid metabolism in chemotherapy resistance remains to be elucidated. This study compared metabolite profiles of sulfur amino acid metabolism from methionine to taurine or glutathione (GSH) between normal MCF-7 and TAM-resistant MCF-7 (TAMR-MCF-7) cells. TAMR-MCF-7 cells showed elevated levels and activities of enzymes involved in both transsulfuration from methionine to cysteine and metabolism of cysteine to GSH and taurine. Cysteine concentrations in TAMR-MCF-7 cells and medium conditioned by cell culture for 42h were markedly decreased, while GSH, hypotaurine, and taurine concentrations in the medium were increased. These results show that TAMR-MCF-7 cells display enhanced cysteine utilization. The addition of propargylglycine, a specific cystathionine γ-lyase inhibitor, and buthionine sulfoximine, a specific γ-glutamylcysteine ligase inhibitor, to TAMR-MCF-7 cells, but not to MCF-7 cells, resulted in cytotoxicity after sulfur amino acid deprivation. These results suggest that cell viability of TAMR-MCF-7 cells is affected by inhibition of sulfur amino acid metabolism, particularly cysteine synthesis from homocysteine and GSH synthesis from cysteine. Additionally, the S-adenosylmethionine/S-adenosylhomocysteine ratio, an index of transmethylation potential, in TAMR-MCF-7 cells increased to ~3.6-fold relative to that in MCF-7 cells, a finding that may result from upregulation of methionine adenosyltransferase IIa and S-adenosylhomocysteine hydrolase. In conclusion, this study suggests that TAMR-MCF-7 cells display enhanced cysteine utilization for synthesis of GSH and taurine, and are sensitive to inhibition of cysteine metabolism.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Chang Seon
authors.initials: CS
authors.lastname: Ryu
authors.forename: Hui Chan
authors.initials: HC
authors.lastname: Kwak
authors.forename: Ji-Yoon
authors.initials: JY
authors.lastname: Lee
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
authors.forename: Nguyen Thi Thuy
authors.initials: NT
authors.lastname: Phuong
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
authors.forename: Sang Kyum
authors.initials: SK
authors.lastname: Kim
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D049990:Membrane Transport Modulators / Q000494:pharmacology; D008715:Methionine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D013654:Taurine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D003542:Cystathionine gamma-Lyase; D003545:Cysteine; D004791:Enzyme Inhibitors; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D049990:Membrane Transport Modulators; D008715:Methionine; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D012435:S-Adenosylhomocysteine; D012436:S-Adenosylmethionine; D013629:Tamoxifen; D013654:Taurine; C003949:hypotaurine