Methionine-stress: A pleiotropic approach in enhancing the efficacy of chemotherapy

2006 ◽  
Vol 233 (2) ◽  
pp. 195-207 ◽  
Author(s):  
Demetrius M. Kokkinakis
Keyword(s):  
Methionine Stress

Hyperhomocysteinemia and Low Methionine Stress Are Risk Factors for Central Retinal Venous Occlusion in an Indian Population

2007 ◽  
Vol 48 (4) ◽  
pp. 1441 ◽  
Author(s):  
Angayarkanni Narayanasamy ◽  
Barathi Subramaniam ◽  
Coral Karunakaran ◽  
Punitham Ranganathan ◽  
Ramakrishnan Sivaramakrishnan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Indian Population ◽  
Venous Occlusion ◽  
Methionine Stress

scholarly journals Methionine stress induces a ferroptotic gene signature in methionine dependent cancer cells

2020 ◽  
Author(s):  
Katherine Wallis ◽  
Jordan T. Bird ◽  
Allen Gies ◽  
Sam G. Mackintosh ◽  
Alan J. Tackett ◽  
...  
Keyword(s):  
Stress Response ◽  
Oxidative Phosphorylation ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cell Line ◽  
Gene Promoters ◽  
Integrated Stress Response ◽  
Normal Cells ◽  
Methionine Restriction ◽  
Methionine Stress

ABSTRACTDietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood, except for the observation that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We found that replacing methionine with homocysteine generally induced hypomethylation in gene promoters. We isolated nuclear proteins and submitted it for tandem mass tag (TMT) proteomics. This analysis revealed that several proteins involved in the mitochondrial integrated stress response (ISR) were upregulated in response to the replacement of methionine to homocysteine in both cell lines, but to a much greater degree in the methionine dependent cell line. Consistent with the ISR signature, a proteomic analysis of a subcellular fraction enriched for mitochondrial content revealed a strong enrichment for proteins involved in oxidative phosphorylation. Analysis of cellular bioenergetics confirmed that homocysteine induces a decrease in ATP production from oxidative phosphorylation and glycolysis, but to a similar extent in methionine dependent and methionine independent cells. The mitochondrial integrated stress response shared a signature with ferroptosis. Methionine dependent cells displayed a strong ferroptotic signature, which was decreased by half in methionine independent cells. Consistent with ferroptosis, lipid peroxidation was significantly increased in methionine independent cells grown in homocysteine, and viability could be rescued partially but significantly with the inhibitor ferrostatin. Therefore, we propose that methionine stress induces ferroptotic cell death in methionine dependent cancer cells.

scholarly journals 4006 Methionine Dependence in Cancer: From Metabolic Phenotype to Therapy

2020 ◽  
Vol 4 (s1) ◽  
pp. 12-12
Author(s):  
Isabelle Miousse
Keyword(s):  
Weight Loss ◽  
Animal Models ◽  
Cancer Cells ◽  
Cell Lines ◽  
Drug Targets ◽  
Metabolic Phenotype ◽  
Methionine Restriction ◽  
Methionine Dependence ◽  
Methionine Stress

OBJECTIVES/GOALS: Methionine dependence was described 45 years ago as an increased reliance on an exogenous supply of the essential amino acid methionine in most cancer cells compared to normal cells. Methionine depletion, using either synthetic diets or the enzyme methioninase, potentiates the effects of chemotherapy and radiotherapy in tumor-bearing animal models. Two main obstacles prevent methionine dependence from integrating the clinical treatment of cancer. The first is the weight loss associated with methionine depletion therapy, increasing the risk of cachexia in patients. The second is the stubborn absence of a mechanism to explain the inability of cancer cells to adapt to low methionine levels. METHODS/STUDY POPULATION: To address these two obstacles, we are using an immunocompetent murine model of metastatic melanoma to compare the effects of complete methionine deprivation with a moderate, 75-80% methionine restriction similar to the one used to increase lifespan in animal models. In an effort to identify a mechanism of action, we also performed a proteomic screen of two melanoma cell lines divergent for methionine dependence under methionine stress. RESULTS/ANTICIPATED RESULTS: We recently showed that methionine restriction is sufficient to provide gains in treating local and metastatic lesions in vivo, without weight loss. We observed few differences in pathway activation between the two cell lines in response to methionine stress, despite proliferation being cut by half in the methionine dependent cell line. We expect that subcellular translocation events may provide further information on the molecular bases of methionine dependence. DISCUSSION/SIGNIFICANCE OF IMPACT: A moderate restriction in methionine is sufficient to recapitulate the benefits of methionine depletion in cancer, without weight loss. The mechanism behind this effect remains unknown. This work contributes towards the integration of methionine dependence into clinical practice and the discovery of novel drug targets.

scholarly journals Downregulation of Cdc6 and pre-replication complexes in response to methionine stress in breast cancer cells

Cell Cycle ◽  
2012 ◽  
Vol 11 (23) ◽  
pp. 4414-4423 ◽  
Author(s):  
Keith Booher ◽  
Da-Wei Lin ◽  
Stacey L. Borrego ◽  
Peter Kaiser
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Methionine Stress

scholarly journals Metabolic changes associated with methionine stress sensitivity in MDA-MB-468 breast cancer cells

2016 ◽  
Vol 4 (1) ◽  
Author(s):  
Stacey L. Borrego ◽  
Johannes Fahrmann ◽  
Rupsa Datta ◽  
Chiara Stringari ◽  
Dmitry Grapov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Stress Sensitivity ◽  
Metabolic Changes ◽  
Methionine Stress

scholarly journals Lipid remodeling in response to methionine stress in MDA-MBA-468 triple-negative breast cancer cells

2021 ◽  
Vol 62 ◽  
pp. 100056
Author(s):  
Stacey L. Borrego ◽  
Johannes Fahrmann ◽  
Jue Hou ◽  
Da-Wei Lin ◽  
Bruce J. Tromberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Methionine Stress
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