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UDP-glucose pyrophosphorylase 2 (UGP2), the enzyme that synthesizes uridine diphosphate (UDP)-glucose, rests at the convergence of multiple metabolic pathways, however, the role of UGP2 in tumor maintenance and cancer metabolism remains unclear. Here, we identify an important role for UGP2 in the maintenance of pancreatic ductal adenocarcinoma (PDAC) growth in both in vitro and in vivo tumor models. We found that transcription of UGP2 is directly regulated by the Yes-associated protein 1 (YAP)–TEA domain transcription factor (TEAD) complex, identifying UGP2 as a bona fide YAP target gene. Loss of UGP2 leads to decreased intracellular glycogen levels and defects in N-glycosylation targets that are important for the survival of PDACs, including the epidermal growth factor receptor (EGFR). These critical roles of UGP2 in cancer maintenance, metabolism, and protein glycosylation may offer insights into therapeutic options for otherwise intractable PDACs.

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP - glucose pyrophosphorylase ( UGP2 ) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.

Breast cancer represents the most prevalent malignancy in women globally. While UDP-glucose pyrophosphorylase 2 (UGP2) has been implicated in tumor biology, its pathophysiological role in breast carcinogenesis remains undefined. This study systematically investigates the clinical relevance and functional mechanisms of UGP2 in breast cancer progression. Multi-omics analysis was conducted using GEPIA2, TIMER2, and TCGA databases to evaluate UGP2 expression patterns, clinicopathological correlations, and prognostic significance across breast cancer subtypes. Findings were validated through immunohistochemical analysis of 118 clinical specimens. Single-cell RNA sequencing data from GEO were employed to resolve UGP2 spatial distribution within tumor microenvironments. Functional enrichment analysis elucidated UGP2-associated pathways, while loss-of-function experiments using siRNA-mediated knockdown assessed UGP2’s impact on malignant phenotypes in breast cancer cell lines. Our research found that the expression level of UGP2 in the TNBC subtype was significantly higher than that in other subtypes. The elevated expression level of UGP2 suggests a poor prognosis for breast cancer patients. The high expression level of UGP2 is positively correlated with the level of CNV. UGP2 is mainly located in epithelial cells and CAFs subsets and can participate in biological processes such as collagen synthesis. Knockdown of UGP2 in vitro can inhibit the proliferation, migration and invasion abilities of breast cancer cells. This study demonstrates that elevated UGP2 expression is clinically associated with aggressive tumor behavior and unfavorable prognosis in breast cancer patients, particularly in the triple-negative subtype (TNBC). Mechanistic analyses reveal UGP2’s functional involvement in both tumor cell proliferation and stromal remodeling through cancer-associated fibroblast (CAF) interactions. The robust association between UGP2 overexpression and aggressive clinicopathological features positions it as both a promising prognostic biomarker and potential therapeutic target, particularly in TNBC management.

The aim of this study was to investigate the hepatoprotection of Schisandra chinensis Caulis polysaccharides (SCPs) in the nonalcoholic fatty liver disease (NAFLD) induced by high-fat diet (HFD) in rats. A total of 30 Wistar rats were randomly divided into the control group (CON), model group (MOD), and Schisandra chinensis caulis polysaccharide (SCP) group. Except for those in the CON group, the other rats were fed with high-fat diet for 4 weeks to establish an NAFLD model. From the 5th week, rats in the SCP group were given SCP solution (100 mg kg −1 ) by gavage for 6 weeks, and those in the CON and MOD groups were given an equal volume of distilled water in the same way. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) levels in serum, the malondialdehyde (MDA) level, glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) activities in the liver tissue were detected. The small molecular metabolites in the blood of rats were determined by the metabolomics method of ultra-high-performance liquid chromatography-quadrupole/electrostatic field orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap-MS/MS) combined with multivariate analysis. The enrichment analysis and pathway analysis of the different metabolites were carried out. The therapeutic mechanism of SCP in NAFLD rats was verified by western blot. The results showed that the levels of AST, ALT, TG, TC, and LDL-C in the serum of rats in the SCP group were significantly lower, and the levels of HDL-C were significantly higher than those in the MOD group. The screening and analysis of the metabolic pathways showed that SCP could alleviate the development of NAFLD by regulating the expression of UDP-glucose pyrophosphorylase (UGP2), UDP-glucose 6-dehydrogenase (UGDH), acetyl CoA carboxylase (ACC), and fatty acid synthase (FAS) in the liver of NAFLD rats. This study may provide a theoretical basis for the development and utilization of SCP.

To minimize treatment toxicities, recent anti-cancer research efforts have switched from broad-based chemotherapy to targeted therapy, and emerging data show that altered cellular metabolism in cancerous cells can be exploited as new venues for targeted intervention. In this study, we focused on, among the altered metabolic processes in cancerous cells, altered glycosylation due to its documented roles in cancer tumorigenesis, metastasis and drug resistance. We hypothesize that the enzymes required for the biosynthesis of UDP-hexoses, glycosyl donors for glycan synthesis, could serve as therapeutic targets for cancers. Through structure-based virtual screening and kinetic assay, we identified a drug-like chemical fragment, GAL-012, that inhibit a small family of UDP-hexose pyrophosphorylases-galactose pyro-phosphorylase (GALT), UDP-glucose pyrophosphorylase (UGP2) and UDP-N-acetylglucosamine pyrophosphorylase (AGX1/UAP1) with an IC50 of 30 µM. The computational docking studies supported the interaction of GAL-012 to the binding sites of GALT at Trp190 and Ser192, UGP2 at Gly116 and Lys127, and AGX1/UAP1 at Asn327 and Lys407, respectively. One of GAL-012 derivatives GAL-012-2 also demonstrated the inhibitory activity against GALT and UGP2. Moreover, we showed that GAL-012 suppressed the growth of PC3 cells in a dose-dependent manner with an EC50 of 75 µM with no effects on normal skin fibroblasts at 200 µM. Western blot analysis revealed reduced expression of pAKT (Ser473), pAKT (Thr308) by 77% and 72%, respectively in the treated cells. siRNA experiments against the respective genes encoding the pyrophosphorylases were also performed and the results further validated the proposed roles in cancer growth inhibition. Finally, synergistic relationships between GAL-012 and tunicamycin, as well as bortezomib (BTZ) in killing cultured cancer cells were observed, respectively. With its unique scaffold and relatively small size, GAL-012 serves as a promising early chemotype for optimization to become a safe, effective, multi-target anti-cancer drug candidate which could be used alone or in combination with known therapeutics.

Background This study investigated UGP2 (uridine diphosphate-glucose pyrophosphorylase-2) and CFL1 (cofilin-1) expression in pancreatic ductal carcinoma (PDC), paracancerous tissue (PT), benign lesions (BL), and normal tissue (NT) and their clinicopathological significance. Methods Surgical specimens, which were collected from 106 cases of pancreatic ductal carcinoma, 35 cases of paracancerous tissues, 55 cases of benign lesions and 13 cases of normal pancreatic tissues, were fixed with 4% formaldehyde to prepare conventional paraffin-embedded sections. EnVision immunohistochemical was used to stain for UGP2 and CFL1. Kaplan-Meier survival analysis was performed to assess the correlation of expression pattern with survival. Results We found that positive UGP2 and CFL1 expression in PDC were significantly higher than those in PT, BL, and NT. In PT and BL with positive UGP2 and CFL1 expression, mild to severe atypical hyperplasia or intraepithelial neoplasia of grades II–III was observed in ductal epithelium. Positive UGP2 and CFL1 expression in cases with high differentiation, no lymph node metastasis, no surrounding invasion, and TNM (tumor-node-metastasis) staging I or/and II were significantly lower than those in cases with poor differentiation, lymph node metastasis, surrounding invasion, and TNM stage III and/or IV. Positive UGP2 expression in male patients was significantly lower than that in female patients. UGP2 and CFL1 expression in PDC were positively correlated. Kaplan-Meier survival analysis showed the degree of differentiation, tumor maximal diameter, TNM stage, lymph node metastasis, and surrounding invasion, and UGP2 and CFL1 expression were closely related to the average survival time of patients with PDC. The survival time of patients with positive UGP2 and CFL1 expression was significantly shorter than that of patients with negative expression. Cox multivariate analysis showed that poor differentiation, tumor maximal diameter ≥ 3 cm, TNM stage III or IV, lymph node metastasis, surrounding invasion, and positive UGP2 and CFL1 expression was negatively correlated with the postoperative survival rate and positively correlated with the mortality of patients with PDC. Conclusion Positive expression of UGP2 and CFL1 can serve a valuable prognostic factor in pancreatic cancer.

UDP-glucose (UDP-Glc) is synthesized by UGP2-encoded UDP-Glc pyrophosphorylase (UGP) and is required for glycoconjugate biosynthesis and galactose metabolism because it is a uridyl donor for galactose-1-P (Gal1P) uridyltransferase. Chinese hamster lung fibroblasts harboring a hypomrphic UGP(G116D) variant display reduced UDP-Glc levels and cannot grow if galactose is the sole carbon source. Here, these cells were cultivated with glucose in either the absence or presence of galactose in order to investigate glycoconjugate biosynthesis and galactose metabolism. The UGP-deficient cells display < 5% control levels of UDP-Glc/UDP-Gal and > 100-fold reduction of [6-3H]galactose incorporation into UDP-[6-3H]galactose, as well as multiple deficits in glycoconjugate biosynthesis. Cultivation of these cells in the presence of galactose leads to partial restoration of UDP-Glc levels, galactose metabolism and glycoconjugate biosynthesis. The Vmax for recombinant human UGP(G116D) with Glc1P is 2000-fold less than that of the wild-type protein, and UGP(G116D) displayed a mildly elevated Km for Glc1P, but no activity of the mutant enzyme towards Gal1P was detectable. To conclude, although the mechanism behind UDP-Glc/Gal production in the UGP-deficient cells remains to be determined, the capacity of this cell line to change its glycosylation status as a function of extracellular galactose makes it a useful, reversible model with which to study different aspects of galactose metabolism and glycoconjugate biosynthesis.