Targeting the methionine addiction of cancer

Methionine is the initiator amino acid for protein synthesis, the methyl source for most nucleotide, chromatin, and protein methylation, and the carbon backbone for various aspects of the cellular antioxidant response and nucleotide biosynthesis. Methionine is provided in the diet and serum methionine levels fluctuate based on dietary methionine content. Within the cell, methionine is recycled from homocysteine via the methionine cycle, which is linked to nutrient status via one-carbon metabolism. Unlike normal cells, many cancer cells, both in vitro and in vivo, show high methionine cycle activity and are dependent on exogenous methionine for continued growth. However, the molecular mechanisms underlying the methionine dependence of diverse malignancies are poorly understood. Methionine deprivation initiates widespread metabolic alterations in cancer cells that enable them to survive despite limited methionine availability, and these adaptive alterations can be specifically targeted to enhance the activity of methionine deprivation, a strategy we have termed "metabolic priming". Chemotherapy-resistant cell populations such as cancer stem cells, which drive treatment-resistance, are also sensitive to methionine deprivation, suggesting dietary methionine restriction may inhibit metastasis and recurrence. Several clinical trials in cancer are investigating methionine restriction in combination with other agents. This review will explore new insights into the mechanisms of methionine dependence in cancer and therapeutic efforts to translate these insights into enhanced clinical activity of methionine restriction in cancer.