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: Chang Seon Ryu, Hui Chan Kwak, Ji-Yoon Lee, Soo Jin Oh, Nguyen Thi Thuy Phuong, Keon Wook Kang, Sang Kyum Kim
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 85 Issue 2 Pg. 197-206 (Jan 15 2013) ISSN: 1873-2968 [Electronic] England
• PMID: 23123664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents, Hormonal
• Enzyme Inhibitors
• Membrane Transport Modulators
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• Tamoxifen
• Taurine
• hypotaurine
• S-Adenosylmethionine
• S-Adenosylhomocysteine
• Methionine
• Cystathionine gamma-Lyase
• Glutamate-Cysteine Ligase
• Glutathione
• Cysteine

Topics

• Antineoplastic Agents, Hormonal (pharmacology)
• Breast Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cystathionine gamma-Lyase (antagonists & inhibitors, metabolism)
• Cysteine (metabolism)
• Drug Resistance, Neoplasm
• Enzyme Inhibitors (pharmacology)
• Female
• Glutamate-Cysteine Ligase (antagonists & inhibitors, metabolism)
• Glutathione (metabolism)
• Humans
• Membrane Transport Modulators (pharmacology)
• Methionine (metabolism)
• Methylation (drug effects)
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (antagonists & inhibitors, metabolism)
• Neoplasm Proteins (antagonists & inhibitors, metabolism)
• S-Adenosylhomocysteine (metabolism)
• S-Adenosylmethionine (metabolism)
• Tamoxifen (pharmacology)
• Taurine (analogs & derivatives, metabolism)
• Up-Regulation (drug effects)