Methionine Dependency and Restriction in Cancer: Exploring the Pathogenic Function and Therapeutic Potential

Abstract

Methionine, an essential amino acid, is obtained by dietary intake to fulfill the requirements of our bodies. Accumulating evidence indicates that methionine plays a pivotal role in various biological processes, including protein synthesis, energy metabolism, redox balance maintenance, and methylation modifications. Numerous advances underscore the heightened dependence of cancer cells on methionine, which is a significant factor in cancer pathogenesis and development. A profound comprehension of the intricate relationship between methionine metabolism and tumorigenesis is imperative for advancing the field of cancer therapeutics. Herein, we delve into the role of methionine in supporting cancer growth, the impact on epigenetic modifications, and the interaction between methionine and the tumor microenvironment. Additionally, we provide insights into the development of various methionine-targeted therapy strategies. This paper summarizes the current state of research and its translational potential, emphasizing the challenges and opportunities associated with harnessing methionine dependence as a target for innovative cancer treatments.

Keywords: cancer; epigenetic modification; methionine metabolism; methionine restriction; tumor microenvironment.

Figure 1

Methionine metabolism pathway. Methionine adenosyltransferases (MATs) catalyze the conversion of methionine and ATP into S-adenosylmethionine (SAM). Methyltransferases (MTs) mediate SAM transmethylation, generating S-adenosylhomocysteine (SAH). Alternatively, SAM undergoes decarboxylation via SAM decarboxylase (SAMDC), yielding decarboxylated SAM (dcSAM). Adenosylhomocysteinase (AHCY) hydrolyzes SAH, producing homocysteine and adenosine. Cystathionine-β-synthase (CBS) converts homocysteine into cystathionine in the transsulfuration pathway; subsequent cleavage yields cysteine. Homocysteine is remethylated to methionine by methionine synthase (MS), completing the methionine cycle. Alternatively, betaine–homocysteine methyltransferase (BHMT) utilizes betaine to remethylate homocysteine, generating methionine. In the methionine salvage pathway, methylthioadenosine phosphorylase (MTAP) reconverts 5-methylthioadenosine (MTA) into methionine. Within the folate cycle, methyl group transfer occurs sequentially between three key folate derivatives: tetrahydrofolate (THF), 5,10-methylenetetrahydrofolate (5,10-MTHF), and 5-methyltetrahydrofolate (5-MTHF). The 5-MTHF-derived methyl group remethylates homocysteine, thereby closing the methionine cycle. Serine hydroxymethyltransferase (SHMT) irreversibly cleaves serine into glycine and 5,10-MTHF.

Figure 2

The relationship between methionine restriction and synthetic lethality. The inefficacy of utilizing MTA leads to its substantial accumulation in MTAP-deficient cancer cells. Subsequently, inhibiting MAT2A can diminish SAM production, effectively impeding the activity of PRMT5 and thereby prompting tumor cell death. Vertical black arrows indicate participation in promoting this process, while red arrows indicate inhibition.

Figure 3

The relationship between methionine and tumor microenvironment. Methionine exerts an inhibitory effect on the anti-tumor immune function of immune cells by influencing the dynamics of the tumor microenvironment. Decreased SAM levels compromise the immune function of CD8+ T cells, upregulate PD-1 expression in CD4+ T cells, and impair the proliferation and cytokine production of CD4+ Th cells.