Guanine monophosphate synthase-mediated nuclear and mitochondrial communication in the progression of gastric cancer.

Abstract

Background: Aberrant regulation of guanine monophosphate synthase (GMPS) and serine hydroxymethyltransferase 2 (SHMT2) has been associated with abnormal cell growth, survival, and death in cancer models. This research endeavors to elucidate how the interplay between GMPS and SHMT2 in the nucleus and mitochondria can affect the viability, programmed cell death, and mitochondrial self-degradation of neoplastic cells.

Methods: The study utilized bioinformatics analysis to investigate the interaction mechanism between GMPS and SHMT2. Subsequently, enzyme-linked immunosorbent assay was utilized to assess the levels of GMPS, SHMT2, and TP53 in serum samples obtained from both gastric cancer (GC) patients and control subjects. Furthermore, the study examined the impact of GMPS knockout on cell characteristics, cellular mitochondrial reactive oxygen species (ROS) and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) levels, as well as the expression of SHMT2, CASP3, and TP53 in GC cell lines AGS, MGC-803, and HGC-27. Additionally, the study detected protein expression levels of TP53, CASP3, and PINK1.

Results: The findings of the bioinformatics analysis revealed a significant upregulation of GMPS, SHMT2, TP53, and CASP3 expression levels in patients diagnosed with gastric carcinoma compared to those in healthy individuals. Additionally, a notable increase in GMPS and SHMT2 expression was observed in cancerous tissues in comparison to adjacent para-carcinoma tissues. Furthermore, the serum levels of GMPS and SHMT2 exhibited significant correlations with the extent of GC invasion, tumor-node-metastasis classification staging, and the administration of chemotherapy (P<0.05); the serum level of TP53, however, was significantly correlated only with the extent of GC invasion and whether chemotherapy was administered (P<0.05). Upon transfection with the pLenti-GMPS-sgRNA plasmid, a notable decrease in the proliferation and migration capabilities of AGS, MGC-803, and HGC-27 cells was observed (P<0.05). Subsequent GMPS knockout resulted in elevated levels of mitochondrial ROS in AGS, MGC-803, and HGC-27 cells, with a particularly significant difference noted in HGC-27 cells. Furthermore, spatial interactions between GMPS and SHMT2, CASP3, and TP53 were identified. Following GMPS knockout, the population of double-positive cells for SHMT2, CASP3, and TP53 experienced a significant reduction (P<0.001). Following GMPS knockout, the protein expression levels of TP53, P-TP53 (Ser15), CASP3, PINK1, and PARK2 were upregulated in AGS cells, while the expression levels of SHMT2, AKT1, and CASP9 proteins were downregulated.

Conclusions: The study identifies GMPS as a novel target for the prognosis and chemotherapy sensitivity of GC patients. The interaction between GMPS and SHMT2 enhances the exchange of nuclear and mitochondrial information in GC cells.