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

• Published in: Biomolecules (Basel, Switzerland) Switzerland), 2021-02, Vol.11 (2), p.246
• Main Authors: Vitale, Daiana L, Caon, Ilaria, Parnigoni, Arianna, Sevic, Ina, Spinelli, Fiorella M, Icardi, Antonella, Passi, Alberto, Vigetti, Davide, Alaniz, Laura
• Format: Article
• Language: English
• Subjects: Antibodies; Apoptosis; Autophagy; Biomarkers; Breast cancer; Cell growth; Chemotherapy; Confocal microscopy; Cytotoxicity; Dehydrogenases; Detoxification; Drug resistance; Enzymes; Epirubicin; ErbB-2 protein; Extracellular matrix; Flow cytometry; Glucose; Glucose dehydrogenase; Heparan sulfate; hyaluronan; Hyaluronic acid; Metabolism; Phagocytosis; Prognosis; Software; Tumors; UDP-glucose 6-dehydrogenase; UDP-glucose dehydrogenase
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom11020246

UDP-glucose-dehydrogenase (UGDH) synthesizes UDP-glucuronic acid. It is involved in epirubicin detoxification and hyaluronan synthesis. This work aimed to evaluate the effect of UGDH knockdown on epirubicin response and hyaluronan metabolism in MDA-MB-231 breast cancer cells. Additionally, the aim was to determine UGDH as a possible prognosis marker in breast cancer. We studied UGDH expression in tumors and adjacent tissue from breast cancer patients. The prognostic value of UGDH was studied using a public Kaplan-Meier plotter. MDA-MB-231 cells were knocked-down for UGDH and treated with epirubicin. Epirubicin-accumulation and apoptosis were analyzed by flow cytometry. Hyaluronan-coated matrix and metabolism were determined. Autophagic-LC3-II was studied by Western blot and confocal microscopy. Epirubicin accumulation increased and apoptosis decreased during UGDH knockdown. Hyaluronan-coated matrix increased and a positive modulation of autophagy was detected. Higher levels of UGDH were correlated with worse prognosis in triple-negative breast cancer patients that received chemotherapy. High expression of UGDH was found in tumoral tissue from HER2 -patients. However, UGDH knockdown contributes to epirubicin resistance, which might be associated with increases in the expression, deposition and catabolism of hyaluronan. The results obtained allowed us to propose UGDH as a new prognostic marker in breast cancer, positively associated with development of epirubicin resistance and modulation of extracellular matrix.