MAOA suppresses the growth of gastric cancer by interacting with NDRG1 and regulating the Warburg effect through the PI3K/AKT/mTOR pathway

Abstract

Objective Previous studies have indicated that neurotransmitters play important roles in the occurrence and development of gastric cancer. MAOA is an important catecholamine neurotransmitter-degrading enzyme involvedin the degradation of norepinephrine, epinephrine and serotonin. To find a potential therapeutic target for the treatment of gastric cancer, the biological functions of MAOA and the underlying mechanism in gastric cancer need to be explored. Methods The Cancer Genome Atlas(TCGA), Gene Expression Omnibus (GEO) datasets, Kaplan‒Meier (KM) plotter and Oncomine databases were used to identify the differentially expressed genes, which mainly involved the degradation and synthesis enzymes of neurotransmitters in gastric cancer. We also investigated the expression pattern of MAOA in human and mouse tissues and cell lines by immunohistochemistry and Western blottinganalysis. Western blotting, quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and a Seahorse experiment were used to identify the molecular mechanism ofcancer cell glycolysis. MAOA expression and patientsurvival were analysed in the Ren Ji cohort, and univariate and multivariate analyses were performed based on the clinicopathological characteristics of the above samples. Results MAOA expression was significantly downregulatedin gastric cancer tissue and associated with poor patient prognosis. Moreover, the expression level of MAOA in gastric cancer tissue had a close negative correlation with theSUXmax valueof PET-CT in patients. MAOA suppressed tumour growth and glycolysis and promoted cancer cell apoptosis. We also show that MAOA can interact with NDRG1 and regulate glycolysis through suppression of the PI3K/Akt/mTOR pathway. MAOA expression may serve as an independent prognostic factor in gastric cancer patients. Conclusions MAOA attenuated glycolysis and inhibitedthe progression of gastric cancer through the PI3K/Akt/mTOR pathway. Loss of function or downregulation of MAOA can facilitate gastric cancer progression. Overexpression of MAOA and inhibition of the PI3K/Akt/mTOR pathway may provide a potential method for gastric cancer treatment in clinicaltherapeutic regimens.

The FOXO1/G6PC axis promotes gastric cancer progression and mediates 5‐fluorouracil resistance by targeting the PI3K/AKT/mTOR signaling pathway

“…Furthermore, in vivo mouse xenograft and lung metastasis model experiments also verified decreased lung metastases and the expression of related proteins with G6PC inhibition. Abnormalities of the PI3K/AKT/mTOR pathway are observed in the majority of malignancies including GC, and participate in diverse physiological processes such as cell proliferation, metastasis, and chemoresistance 20,21 . Notably, the PI3K/AKT/mTOR pathway was able to promote the carcinogenesis of GC by increasing post‐translational phosphorylation 22 .…”

Serotonin signalling in cancer: Emerging mechanisms and therapeutic opportunities

“…For example, in GC tissues, the expression of MAOA was found to be notably reduced, which correlated with an unfavourable patient prognosis. 192 Substantial evidence indicates that targeting MAOA blocks PCa proliferation and metastasis, [189][190][191] restores enzalutamide sensitivity, 193,194 and revokes immune suppression. 122,195,196 Importantly, clinically available MAOIs, which are utilised in the treatment of depression and various neurological conditions, have demonstrated promising outcomes against PCa in both experimental models and clinical studies, presenting a promising chance for their repurposing as a treatment for PCa.…”

“…While MAOA expression is not universally upregulated in all cancer types. For example, in GC tissues, the expression of MAOA was found to be notably reduced, which correlated with an unfavourable patient prognosis 192 …”

M6A methylation of FKFB3 reduced pyroptosis of gastric cancer by NLRP3

“…This unique glucose metabolism process promotes the malignant transformation of tumors and enhances immune evasion, proliferation, migration and drug resistance in tumor cells [15]. The dysregulated glucose metabolism in tumor cells further increases drug resistance, making the regulation of protein molecules involved in the Warburg effect a crucial factor in overcoming drug resistance [16]. By regulating metabolic pathways such as glucose uptake and lactate production, GC cells create favorable conditions for their proliferation, invasion, metastasis and escape, which helps them to proliferate and survive indefinitely during tumor progression.…”