Glycolysis is the primary method utilized by cancer cells to produce the energy (adenosine triphosphate, ATP) required for cell proliferation. Therefore, inhibition of glycolysis may inhibit tumor growth. We previously found that both 3-bromopyruvate (3-BrPA) and sodium citrate (SCT) can inhibit glycolysis in vitro; however, the underlying inhibitory mechanisms remain unclear. In the present study, we used a human gastric cancer cell line (SGC-7901) and an orthotopic transplantation tumor model in nude mice to explore the specific mechanisms of 3-BrPA and SCT. We found that both 3-BrPA and SCT effectively suppressed cancer cell proliferation, arrested the cell cycle, induced apoptosis, and decreased the production of lactate and ATP. 3-BrPA significantly reduced the glycolytic enzyme hexokinase activity, while SCT selectively inhibited phosphofructokinase-1 activity. Furthermore, 3-BrPA and SCT upregulated the expression of pro-apoptotic proteins (Bax, cytochrome c, and cleaved caspase-3) and downregulated the expression of anti-apoptotic proteins (Bcl-2 and survivin). Finally, our animal model of gastric cancer indicated that intraperitoneal injection of 3-BrPA and SCT suppressed orthotopic transplantation tumor growth and induced tumor apoptosis. Taken together, these results suggest that 3-BrPA and SCT selectively suppress glycolytic enzymes, decrease ATP production, induce mitochondrial-mediated apoptosis, downregulate survivin, and inhibit tumor growth. Moreover, an intraperitoneal injection is an effective form of administration of 3-BrPA and SCT.

Cancer cells are mainly dependent on glycolysis to generate adenosine triphosphate (ATP) and intermediates required for cell growth and proliferation. Thus, inhibition of glycolysis might be of therapeutic value in antitumor treatment. Our previously studies had found that both 3-bromopyruvate (BP) and sodium citrate (SCT) can inhibit tumor growth and proliferation in vitro and in vivo. However, the mechanism involved in the BP and SCT mediated antitumor activity is not entirely clear. In this work, it is demonstrated that BP inhibits the enzyme hexokinase (HK) activity and SCT suppresses the phosphofructokinase (PFK) activity respectively, both the two agents decrease viability, ATP generation and lactate content in the human gastric cancer cell line MGC-803. These effects are directly correlated with blockage of glycolysis. Furthermore, BP and SCT can induce the characteristic manifestations of mitochondria-regulated apoptosis, such as down-regulation of anti-apoptosis proteins Bcl-2 and Survivin, up-regulation of pro-apoptosis protein Bax, activation of caspase-3, as well as leakage of cytochrome c (Cyt-c). In summary, our results provided evidences that BP and SCT inhibit the MGC-803 cells growth and proliferation might be correlated with inhibiting glycolysis and promoting mitochondria-regulated apoptosis.

Background: The role and mechanism of hsa_circRNA_104433 in gastric cancer (GC) are further elucidated. Materials and methods: CircRNA_104433 was selected by circRNA microarrays and GEO database. qRT-PCR was used to analyze the expression of circRNA_104433 in GC. The role of circRNA_104433 in GC cells was evaluated based on cell cycle progression, cell proliferation, cell apoptosis, and tumor xenograft experiment assay. To explore the mechanisms of circRNA_104433 in GC TCGA database, STRING version, qRT-PCR and luciferase assay were performed. Furthermore, the prognostic value of CDC25A in GC was determined based on the GEO database. Results: The level of circRNA_104433 showed upregulation in GC tissues, and the expression of it showed a positive correlation with the degree of differentiation and the size of the tumor. Knockdown of circRNA_104433 inhibited cell cycle transition, and cell proliferation, while promoted cell apoptosis in GC. CircRNA_104433 directly binds to miR-497-5p, which directly regulates CDC25A. The median survival period of GC patients with high expression levels of CDC25A was 21.3 months, which was shorter than those with low group expression of CDC25A (35.9 months). The cell cycle proteins CDK1, CDK2, CCNB1, PKMYT1, CDC20, CHEK1 and CDC25A were coexpressed with CDC25A. Conclusion: These findings suggested that knockdown of circRNA_104433 expression suppressed tumor development in GC.