Methionine restriction in cancer: a dietary insight for therapy

TL;DR

Methionine restriction, a dietary strategy, can target cancer's metabolic vulnerabilities by disrupting essential processes like methylation and redox balance.

Contribution

The paper highlights methionine restriction as a novel therapeutic approach for cancer by exploiting tumor-specific metabolic dependencies.

Findings

Methionine restriction disrupts one-carbon metabolism and epigenetic regulation in tumors.

Combining methionine restriction with existing therapies improves clinical outcomes in various cancers.

Low-methionine diets and enzymatic degradation via methioninase are effective strategies to target methionine addiction in cancer.

Abstract

Methionine, one of the essential amino acids that needs to be obtained through protein-rich diet, provides important sulfur elements for the human body, which is crucial for protein synthesis, antioxidant and metabolic regulation. Many tumors develop a metabolic dependency due to the lack of a working methionine salvage pathway, which can be targeted by methionine restriction (MR).

The core mechanism of MR lies in disrupting one-carbon metabolism and epigenetic regulation that rely on methionine, depleting the crucial metabolite S-adenosylmethionine (SAM), thereby inhibiting histone/DNA methylation, disrupting redox homeostasis, and ultimately inducing cell cycle arrest and apoptosis. Substantial evidence indicates that MR, achieved by specific metabolic enzyme inhibitors or diet with special formulations, can intervene in tumor progression from a metabolic standpoint. Additionally, combining methionine restriction with existing treatments can achieve satisfactory outcomes in the clinical management of various tumors.

This article provides insights into the research and its translational potential of methionine restriction as a promising strategy for cancer treatment, with the emphasis on the contributions that advance the field and better serve the clinical research community.

Targeting the methionine addiction of cancer: a precision strategy against a metabolic vulnerability. Reactive oxygen species (ROS), Glutathione (GSH); S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), Protein arginine methyltransferase 5 (PRMT5), Methylthioadenosine phosphorylase (MTAP), Methylthioadenosine (MTA), Methionine (Met), Oral recombinant methioninase (Oral rMETase), Methionine adenosyltransferase 2A (MAT2A), MAT2A inhibitor AG-270 (AG-270), PRMT5 inhibitor AMG 193 (AMG 193).Diagram illustrating the dependence of tumor cells on exogenous methionine and related therapeutic strategies. The inner circle shows a tumor cell lacking MTAP, common in about 15% of cancers. Methionine reduction leads to effects like hypomethylation, polyamine synthesis disruption, and dysregulated gene expression. Therapeutic strategies include dietary intervention with low-methionine diets, enzymatic degradation via methioninase, and pharmacotherapy targeting PRMT5 and MAT2A. These approaches aim to induce cancer cell death and disrupt proliferation, often in combination with chemotherapy, radiotherapy, or immunotherapy.

Targeting the methionine addiction of cancer: a precision strategy against a metabolic vulnerability. Reactive oxygen species (ROS), Glutathione (GSH); S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), Protein arginine methyltransferase 5 (PRMT5), Methylthioadenosine phosphorylase (MTAP), Methylthioadenosine (MTA), Methionine (Met), Oral recombinant methioninase (Oral rMETase), Methionine adenosyltransferase 2A (MAT2A), MAT2A inhibitor AG-270 (AG-270), PRMT5 inhibitor AMG 193 (AMG 193).

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