Initial Identification of UDP-Glucose Dehydrogenase as a Prognostic Marker in Breast Cancer Patients, Which Facilitates Epirubicin Resistance and Regulates Hyaluronan Synthesis in MDA-MB-231 Cells

Vitale, Daiana Luján; Caon, Ilaria; Parnigoni, Arianna; Sevic, Ina; Spinelli, Fiorella Mercedes; Icardi, Antonella; Passi, Alberto; Vigetti, Davide; Alaniz, Laura

doi:10.3390/biom11020246

Cited by 25 publications

(25 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…UGDH may induce resistance to chemotherapy via drug elimination. This was supported by a recent study demonstrating that high levels of UGDH are correlated with worse prognosis in triple‐negative breast cancer patients receiving chemotherapy, likely by promoting UDP‐GlcA‐mediated detoxification and elimination of epirubicin [ 76 ]. The effect of UGDH on SNAI1 supports that UGDH has a regulatory role in EMT and that its function may exceed its catalytic role, perhaps via nonconventional signalling regulatory effects such as glycosylation (Fig.…”

Section: Discussionmentioning

confidence: 64%

UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

et al. 2022

View full text Add to dashboard Cite

Metabolic rewiring is one of the indispensable drivers of epithelial–mesenchymal transition (EMT) involved in breast cancer metastasis. In this study, we explored the metabolic changes during spontaneous EMT in three separately established breast EMT cell models using a proteomic approach supported by metabolomic analysis. We identified common proteomic changes, including the expression of CDH1, CDH2, VIM, LGALS1, SERPINE1, PKP3, ATP2A2, JUP, MTCH2, RPL26L1 and PLOD2. Consistently altered metabolic enzymes included the following: FDFT1, SORD, TSTA3 and UDP‐glucose dehydrogenase (UGDH). Of these, UGDH was most prominently altered and has previously been associated with breast cancer patient survival. siRNA‐mediated knock‐down of UGDH resulted in delayed cell proliferation and dampened invasive potential of mesenchymal cells and downregulated expression of the EMT transcription factor SNAI1. Metabolomic analysis revealed that siRNA‐mediated knock‐down of UGDH decreased intracellular glycerophosphocholine (GPC), whereas levels of acetylaspartate (NAA) increased. Finally, our data suggested that platelet‐derived growth factor receptor beta (PDGFRB) signalling was activated in mesenchymal cells. siRNA‐mediated knock‐down of PDGFRB downregulated UGDH expression, potentially via NFkB‐p65. Our results support an unexplored relationship between UGDH and GPC, both of which have previously been independently associated with breast cancer progression.

show abstract

Section: Discussionmentioning

confidence: 64%

UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Intracellular glucose levels were unchanged across all R7 modulations and not detected in MRBC cell lines, but lactate levels were significantly reduced upon RON or β-catenin loss not with DEK loss ( Fig 1C ). An alternative utilization of glucose for glycogen synthesis and the addition of glucose to other biomolecules involves uridine diphosphate (UDP) conjugation of glucose, which is implicated in supporting breast cancer migration, metastasis, and treatment resistance [ 28 , 29 ]. UDP-glucose levels were ablated upon DEK loss ( Fig 1C ).…”

Section: Resultsmentioning

confidence: 99%

NMR-based metabolomic analysis identifies RON-DEK-β-catenin dependent metabolic pathways and a gene signature that stratifies breast cancer patient survival

et al. 2022

View full text Add to dashboard Cite

Background Advances in detection techniques and treatment have increased the diagnosis of breast cancer at early stages; however, recurrence occurs in all breast cancer subtypes, and both recurrent and de novo metastasis are typically treatment resistant. A growing body of evidence supports the notion that metabolic plasticity drives cancer recurrence. RON and DEK are proteins that promote cancer metastasis and synergize mechanistically to activate β-catenin, but the metabolic consequences are unknown. Methods To ascertain RON-DEK-β-catenin dependent metabolic pathways, we utilized an NMR-based metabolomics approach to determine steady state levels of metabolites. We also interrogated altered metabolic pathway gene expression for prognostic capacity in breast cancer patient relapse-free and distant metastasis-free survival and discover a metabolic signature that is likely associated with recurrence. Results RON-DEK-β-catenin loss showed a consistent metabolite regulation of succinate and phosphocreatine. Consistent metabolite alterations between RON and DEK loss (but not β-catenin) were found in media glucose consumption, lactate secretion, acetate secretion, and intracellular glutamine and glutathione levels. Consistent metabolite alterations between RON and β-catenin loss (and not DEK) were found only in intracellular lactate levels. Further pathway hits include β-catenin include glycolysis, glycosylation, TCA cycle/anaplerosis, NAD+ production, and creatine dynamics. Genes in these pathways epistatic to RON-DEK-β-catenin were used to define a gene signature that prognosticates breast cancer patient survival and response to chemotherapy. Conclusions The RON-DEK-β-catenin axis regulates the numerous metabolic pathways with significant associations to breast cancer patient outcomes.

show abstract

“…Among the processes controlled by this natural barrier are the modulation of immune effectors (35,113), the inhibition of diffusion of chemotherapeutic drugs (128) and the difficult uptake of DNA transgene complexes in gene therapy (129). Furthermore, previous studies from our laboratory and other authors have shown that ECM components play important roles in acquired resistance to anticancer drugs (34,130,131). Therefore, the development of novel cancer treatments that target HA by altering the ECM represents a pioneering approach to the treatment of several cancers.…”

Section: -Mu Treatment As a New Strategy Of Co-adjuvant Drug On Conventional Antineoplastic Therapiesmentioning

confidence: 99%

Targeting the Tumor Extracellular Matrix by the Natural Molecule 4-Methylumbelliferone: A Complementary and Alternative Cancer Therapeutic Strategy

et al. 2021

Self Cite

View full text Add to dashboard Cite

In antineoplastic therapy, one of the challenges is to adjust the treatment to the needs of each patient and reduce the toxicity caused by conventional antitumor strategies. It has been demonstrated that natural products with antitumoral properties are less toxic than chemotherapy and radiotherapy. Also, using already developed drugs allows developing substantially less costly methods for the discovery of new treatments than traditional drug development. Candidate molecules proposed for drug repositioning include 4-methylumbelliferone (4-MU), an orally available dietetic product, derivative of coumarin and mainly found in the plant family Umbelliferae or Apiaceae. 4-MU specifically inhibits the synthesis of glycosaminoglycan hyaluronan (HA), which is its main mechanism of action. This agent reduces the availability of HA substrates and inhibits the activity of different HA synthases. However, an effect independent of HA synthesis has also been observed. 4-MU acts as an inhibitor of tumor growth in different types of cancer. Particularly, 4-MU acts on the proliferation, migration and invasion abilities of tumor cells and inhibits the progression of cancer stem cells and the development of drug resistance. In addition, the effect of 4-MU impacts not only on tumor cells, but also on other components of the tumor microenvironment. Specifically, 4-MU can potentially act on immune, fibroblast and endothelial cells, and pro-tumor processes such as angiogenesis. Most of these effects are consistent with the altered functions of HA during tumor progression and can be interrupted by the action of 4-MU. While the potential advantage of 4-MU as an adjunct in cancer therapy could improve therapeutic efficacy and reduce toxicities of other antitumoral agents, the greatest challenge is the lack of scientific evidence to support its approval. Therefore, crucial human clinical studies have yet to be done to respond to this need. Here, we discuss and review the possible applications of 4-MU as an adjunct in conventional antineoplastic therapies, to achieve greater therapeutic success. We also describe the main proposed mechanisms of action that promote an increase in the efficacy of conventional antineoplastic strategies in different types of cancer and prospects that promote 4-MU repositioning and application in cancer therapy.

show abstract

Initial Identification of UDP-Glucose Dehydrogenase as a Prognostic Marker in Breast Cancer Patients, Which Facilitates Epirubicin Resistance and Regulates Hyaluronan Synthesis in MDA-MB-231 Cells

Cited by 25 publications

References 62 publications

UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

NMR-based metabolomic analysis identifies RON-DEK-β-catenin dependent metabolic pathways and a gene signature that stratifies breast cancer patient survival

Targeting the Tumor Extracellular Matrix by the Natural Molecule 4-Methylumbelliferone: A Complementary and Alternative Cancer Therapeutic Strategy

Contact Info

Product

Resources

About