title: Sulfur amino acid metabolism in doxorubicin-resistant breast cancer cells.
abstract: Although methionine dependency is a phenotypic characteristic of tumor cells, it remains to be determined whether changes in sulfur amino acid metabolism occur in cancer cells resistant to chemotherapeutic medications. We compared expression/activity of sulfur amino acid metabolizing enzymes and cellular levels of sulfur amino acids and their metabolites between normal MCF-7 cells and doxorubicin-resistant MCF-7 (MCF-7/Adr) cells. The S-adenosylmethionine/S-adenosylhomocysteine ratio, an index of transmethylation potential, in MCF-7/Adr cells decreased to ~10% relative to that in MCF-7 cells, which may have resulted from down-regulation of S-adenosylhomocysteine hydrolase. Expression of homocysteine-clearing enzymes, such as cystathionine beta-synthase, methionine synthase/methylene tetrahydrofolate reductase, and betaine homocysteine methyltransferase, was up-regulated in MCF-7/Adr cells, suggesting that acquiring doxorubicin resistance attenuated methionine-dependence and activated transsulfuration from methionine to cysteine. Homocysteine was similar, which is associated with a balance between the increased expressions of homocysteine-clearing enzymes and decreased extracellular homocysteine. Despite an elevation in cysteine, cellular GSH decreased in MCF-7/Adr cells, which was attributed to over-efflux of GSH into the medium and down-regulation of the GSH synthesis enzyme. Consequently, MCF-7/Adr cells were more sensitive to the oxidative stress induced by bleomycin and menadione than MCF-7 cells. In conclusion, our results suggest that regulating sulfur amino acid metabolism may be a possible therapeutic target for chemoresistant cancer cells. These results warrant further investigations to determine the role of sulfur amino acid metabolism in acquiring anticancer drug resistance in cancer cells using chemical and biological regulators involved in sulfur amino acid metabolism.
authors.affiliation: College of Pharmacy and RCTCP, 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: Kye Sook
authors.initials: KS
authors.lastname: Lee
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
authors.forename: Ki Ho
authors.initials: KH
authors.lastname: Lee
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Jin Yeul
authors.initials: JY
authors.lastname: Ma
authors.forename: Sang Kyum
authors.initials: SK
authors.lastname: Kim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000603:Amino Acids, Sulfur / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D003545:Cysteine / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008715:Methionine / Q000378:metabolism; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000603:Amino Acids, Sulfur; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D024483:Vitamin K 3; D004317:Doxorubicin; D008715:Methionine; D005978:Glutathione; D003545:Cysteine