Methionine Deprivation Induces a Targetable Vulnerability in Triple-Negative Breast Cancer Cells by Enhancing TRAIL Receptor-2 Expression.
OBJECTIVE
Many neoplasms are vulnerable to methionine deficiency by mechanisms that are poorly understood. Because gene profiling studies have revealed that methionine depletion increases TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) mRNA, we postulated that methionine stress sensitizes breast cancer cells to proapoptotic TRAIL-R2 agonists.


METHODS
Human triple (ER/PR/HER2)-negative breast carcinoma cell lines were cultured in control or methionine-free media. The effects of methionine depletion on TRAIL receptor expression and sensitivity to chemotherapy or a humanized agonistic TRAIL-R2 monoclonal antibody (lexatumumab) were determined. The melanoma-associated antigen MAGED2 was silenced to delineate its functional role in sensitizing TNBC cells to methionine stress. An orthotopic TNBC model was utilized to evaluate the effects of dietary methionine deficiency, lexatumumab, or the combination.


RESULTS
Methionine depletion sensitized TNBC cells to lexatumumab-induced caspase activation and apoptosis by increasing TRAIL-R2 mRNA and cell surface expression. MCF-10A cells transformed by oncogenic H-Ras, but not untransformed cells, and matrix-detached TNBC cells were highly sensitive to the combination of lexatumumab and methionine depletion. Proteomics analyses revealed that MAGED2, which has been reported to reduce TRAIL-R2 expression, was suppressed by methionine stress. Silencing MAGED2 recapitulated features of methionine deprivation, including enhanced mRNA and cell surface expression of TRAIL receptors and increased sensitivity to TRAIL receptor agonists. Dietary methionine deprivation enhanced the antitumor effects of lexatumumab in an orthotopic metastatic TNBC model.


CONCLUSIONS
Methionine depletion exposes a targetable defect in TNBC cells by increasing TRAIL-R2 expression. Our findings provide the foundation for a clinical trial combining dietary methionine restriction and TRAIL-R2 agonists. Clin Cancer Res; 21(12); 2780-91. ©2015 AACR.
Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Elena
E
Strekalova
Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Dmitry
D
Malin
Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
David M
DM
Good
Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. vlcryns@medicine.wisc.edu.
Vincent L
VL
Cryns
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008715:Methionine / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; C451414:MAGED2 protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C510234:lexatumumab; D008715:Methionine; D020169:Caspases