The Role of Methionine Restriction in Gastric Cancer: A Summary of Mechanisms and a Discussion on Tumor Heterogeneity

Abstract

Gastric cancer is ranked as the fifth most prevalent cancer globally and has long been a topic of passionate discussion among numerous individuals. However, the incidence of gastric cancer in society has not decreased, but instead has shown a gradual increase in recent years. For more than a decade, the treatment effect of gastric cancer has not been significantly improved. This is attributed to the heterogeneity of cancer, which makes popular targeted therapies ineffective. Methionine is an essential amino acid, and many studies have shown that it is involved in the development of gastric cancer. Our study aimed to review the literature on methionine and gastric cancer, describing its mechanism of action to show that tumor heterogeneity in gastric cancer does not hinder the effectiveness of methionine-restricted therapies. This research also aimed to provide insight into the inhibition of gastric cancer through metabolic reprogramming with methionine-restricted therapies, thereby demonstrating their potential as adjuvant treatments for gastric cancer.

Keywords: chemotherapy; gastric cancer; gastric cancer stem cells; helicobacter pylori; heterogeneity; immune response; methionine; programmed cell death.

Figure 1

Methionine cycle. The first step of the methionine cycle is the conversion of methionine into S-adenosylmethionine (SAM) by methionine adenosyltransferase (MAT). SAM is converted into S-adenosyl homocysteine (SAH) after donating a methyl group for methylation reactions. This step is mediated by methyltransferases (MTs). SAH is then hydrolyzed by S-adenosyl-L-homocysteine hydrolase (SAHH) to generate homocysteine. Finally, homocysteine receives a methyl group from the folate cycle or betaine to become methionine; these reactions are mediated by 5-methyltetrahydrofolate: homocysteine methyltransferase (MTR) and betaine-homocysteine methyltransferase (BHMT), respectively. The methionine cycle is interconnected with three important metabolic pathways by providing substrates. These pathways include the folate cycle, the transsulfuration pathway, the methionine salvage pathway, and polyamine synthesis, all of which support important cellular functions. Met: methionine; SAM: S-adenosyl methionine; MAT: Met adenosyltransferase; SAH: S-adenosylhomocysteine; MTs: methyltransferases; Hcy: homocysteine; DMG: dimethylglycine; BHMT: betaine-homocysteine methyltransferase; 5-methyl-THF: 5-methyltetrahydrofolate; THF: tetrahydrofolate; MTR: methyltransferase.

Figure 2

Met plays a pivotal role in the survival and functional repertoire of Hp. Hp infection destroys the mucus layer of the stomach, leading to chronic inflammation within the stomach. During this period, Hp is damaged by both the acidic environment within the stomach and oxidizing factors secreted by inflammatory cells. Hp is able to resist the acidic environment through urease. And it utilizes Met to counteract the antioxidant factors. The S (Met-S) of the Met residue of urease and catalase reacts with oxidizing factors to convert high oxidizing factors to gastric low oxidizing factors, converts itself to Met-SO, and then converts back to Met-S when catalyzed by methionine sulfoxide reductase. Hcy is converted to H2S via three pathways: cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfotransferase (3MST). H₂S is a reducing agent that scavenges oxidizing molecules, including ROS and hydrogen peroxide (H₂O₂). Additionally, H₂S enhances wound healing by facilitating angiogenesis through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Furthermore, H₂S restricts neutrophil migration, inflammation, and oxidative burst.

Figure 3

MR promotes the programmed cell death of gastric cancer cells. In the MR environment, the CDH1 promoter was completely demethylated, upregulating the expression of CDH1 and thus enhancing the expression of E-cadherin and inhibiting the invasive metastasis of gastric cancer. The downregulation of SNHG5 expression and the increase in miR-20a expression promoted the autophagy and apoptosis of gastric cancer cells; the expression of long non-coding RNA (lncRNA) PVT1 was also significantly downregulated, and the interaction between lncRNA PVT1 and DNMT3 was weakened. The expression of long non-coding RNA (lncRNA) PVT1 was also significantly downregulated, and the interaction between lncRNA PVT1, and DNMT3 was weakened, leading to the decrease in the DNA methylation level of the BNIP1 promoter and the upregulation of the level of BNIP3, which suppressed the proliferation of gastric cancer cells and activated the autophagy of mitochondria, leading to the apoptosis of gastric cancer cells.

Figure 4

MR suppresses gastric cancer development by inhibiting GSCSs. MR decreases the methylation of RAB37, resulting in the upregulation of RAB37 expression. Additionally, regulating the miR-200b/PKCα axis indirectly increased the activity of RAB37; then, binding it to autophagy-related gene 5 (ATG5) induced the autophagy of GCSCs. MR decreases the methylation of miR-7, resulting in the upregulation of miR7 expression, leading to the inhibition of epidermal growth factor receptor (EGFR) and nuclear factor-κB (NF-κB) signaling pathways, eventually inhibiting gastric cancer invasion and metastasis. MR activates p53 signaling in GCSCs, selectively triggers apoptosis, and causes a decrease in the DNA methylation level of the miR-7-5p promoter region, thereby further promoting apoptosis in GCSCs.

Figure 5

MR improves chemotherapy efficacy in gastric cancer: MR induces the entry of cancer cells, which are trapped in the G0/G1 phase (low sensitivity to chemotherapeutic agents), into the S/G2 phase (high sensitivity to chemotherapeutic agents). MR downregulates nuclear factor-κB (NF-κB), which leads to the upregulation of tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) expression, followed by the downregulation of P-gp and the death of cancer cells; the downregulation of miR-21 expression, which further enhances the sensitivity of gastric cancer cells to cisplatin and induces the death of cancer cells; and the downregulation of NF-κB, inducing the death of cancer cells.