PUM1 Promotes Tumor Progression by Activating DEPTOR‐Meditated Glycolysis in Gastric Cancer

Abstract

RNA‐binding proteins (RBPs) play essential roles in tumorigenesis and progression, but their functions in gastric cancer (GC) remain largely elusive. Here, it is reported that Pumilio 1 (PUM1), an RBP, induces metabolic reprogramming through post‐transcriptional regulation of DEP domain‐containing mammalian target of rapamycin (mTOR)‐interacting protein (DEPTOR) in GC. In clinical samples, elevated expression of PUM1 is associated with recurrence, metastasis, and poor survival. In vitro and in vivo experiments demonstrate that knockdown of PUM1 inhibits the proliferation and metastasis of GC cells. In addition, RNA‐sequencing and bioinformatics analyses show that PUM1 is enriched in the glycolysis gene signature. Metabolomics studies confirm that PUM1 deficiency suppresses glycolytic metabolism. Mechanistically, PUM1 binds directly to DEPTOR mRNA pumilio response element to maintain the stability of the transcript and prevent DEPTOR degradation through post‐transcriptional pathway. PUM1‐mediated DEPTOR upregulation inhibits mTORC1 and alleviates the inhibitory feedback signal transmitted from mTORC1 to PI3K under normal conditions, thus activating the PI3K–Akt signal and glycolysis continuously. Collectively, these results reveal the critical epigenetic role of PUM1 in modulating DEPTOR‐dependent GC progression. These conclusions support further clinical investigation of PUM1 inhibitors as a metabolic‐targeting treatment strategy for GC.

Calcitriol suppresses gastric cancer progression and cisplatin resistance by inhibiting glycolysis and M2 macrophage polarization through inhibition of mTOR activation

“…The glycolytic pathway is upregulated in various cancers, including gastric cancer, to meet the increased energy demands for rapid cell growth and proliferation. 22 In our study, calcitriol treatment significantly suppressed the expression of glycolysis-related genes and proteins (GLUT1, HKII, LDHA) in MCM-induced gastric cancer cells. This observation is consistent with previous studies demonstrating calcitriol's ability to inhibit glycolysis in different cancer contexts.…”

Analysis of metabolic characteristics of metabolic syndrome in elderly patients with gastric cancer by non-targeted metabolomics

“…Compared with those in the control group, the five amino acids arginylalanine, n-acetylvaline, D-citrulline, L-valic acid, and L-aspartamide in the frail group decreased significantly, which was related to the decrease in muscle mass or strength during the frailty process[ 18 - 20 ]. Based on the MetaboFrail project in Europe, 37 kinds of amino acids were measured in patients with asthenic diabetes and in the asthenic control population, and the specific amino acid metabolism characteristics of elderly patients with asthenic diabetes were revealed[ 21 ]. Amino acids such as glutamine, glutathione, n-acetyl-l-alonic acid, n-valeric acid, and (S)-β-aminoisobutyric acid, which produced significant metabolic changes in the combined group, have been found to be related to tumor initiation, development, treatment, and predensitization[ 22 ].…”