ABSTRACT
Orotate phosphoribosyltransferase (OPRT) is engaged in de novo pyrimidine synthesis. It catalyzes oronitine to uridine monophosphate (UMP), which is used for RNA synthesis. De novo pyrimidine synthesis has long been known to play an important role in providing DNA/RNA precursors for rapid proliferative activity of cancer cells. Furthermore, chemotherapeutic drug 5-fluorouracil (5-FU) is taken up into cancer cells and is converted to 5-fluoro-UMP (FUMP) by OPRT or to 5-fluoro-dUMP (FdUMP) through intermediary molecules by thymidine phosphorylase. These 5-FU metabolites are misincorporated into DNA/RNA, thereby producing dysfunction of these information processing. However, it remains unclear how the subcellular localization of OPRT and how its variable expression levels affect the response to 5-FU at the cellular level. In this study, immunocytochemical analysis reveals that OPRT localizes to the Golgi complex. Results also show that not only overexpression but also downregulation of OPRT render cells susceptible to 5-FU exposure, but it has no effect on DNA damaging agent doxorubicin. This study provides clues to elucidate the cellular response to 5-FU chemotherapy in relation to the OPRT expression level.
Subject(s)
Antineoplastic Agents/pharmacology , Fluorouracil/pharmacology , Golgi Apparatus/drug effects , Orotate Phosphoribosyltransferase/metabolism , Animals , COS Cells , Cell Proliferation/drug effects , Chlorocebus aethiops , DNA Damage/drug effects , Down-Regulation , Doxorubicin/pharmacology , Golgi Apparatus/metabolism , HEK293 Cells , HeLa Cells , Humans , Immunohistochemistry , Orotate Phosphoribosyltransferase/genetics , RNA InterferenceABSTRACT
OBJECTIVE: To clarify the role of glucocorticoid receptor-beta in resistance to glucocorticoid therapy for allergic rhinitis, we studied 37 tissue samples from 20 patients with severe allergic rhinitis, and samples from age-matched controls. METHODS: Patients were treated with intranasal fluticasone for 6 months and inferior turbinectomy was performed for patients with poor response to glucocorticoid treatment. The expression of glucocorticoid receptor-alpha (GR-alpha), glucocorticoid receptor-beta (GR-beta), and nuclear factor-kappaB (NF-kappaB) in nasal mucosa was studied immunohistochemically. RESULTS: GR-alpha and NF-kappaB were expressed to a similar extent in patients and controls, but GR-beta was expressed significantly more in patients, resulting in an increased GR-beta/GR-alpha ratio. CONCLUSION: Our findings suggest that GR-beta plays an important role in resistance to glucocorticoid therapy for allergic rhinitis, and its expression might be used as an additional parameter indicating steroid resistance in allergic rhinitis.
Subject(s)
Androstadienes/therapeutic use , Anti-Inflammatory Agents/therapeutic use , NF-kappa B/analysis , Receptors, Glucocorticoid/analysis , Rhinitis, Allergic, Perennial/pathology , Administration, Intranasal , Adult , Drug Resistance , Female , Fluticasone , Humans , Male , Microscopy, Fluorescence , NF-kappa B/drug effects , Nasal Mucosa/drug effects , Nasal Mucosa/immunology , Nasal Mucosa/pathology , Receptors, Glucocorticoid/drug effects , Reference Values , Rhinitis, Allergic, Perennial/drug therapy , Rhinitis, Allergic, Perennial/immunology , Young AdultABSTRACT
We report a rare case of adenosquamous carcinoma of the larynx. A 38-year-old man with a 9-month history of progressive hoarseness and dyspnea during exercise and sudden-onset breathing difficulty was unable to be intubated and underwent a tracheostomy at the emergency department. He was found in endoscopic examination of the larynx to have a large smooth subglottic mass with laryngeal stenosis. The bilateral vocal cords were fixed. No cervical lymph node was seen. Excisional laryngofissure biopsy led to a pathological diagnosis of adenosquamous carcinoma, necessitating laryngectomy with bilateral neck dissection (Level II-IV) and postoperative radiation therapy. He died of metastatic disease 7.5 years after the initial treatment, without locoregional recurrence. Among malignant laryngeal tumors, adenosquamous carcinoma is extremely rare, with only 33 such cases including ours reported in the literature.
Subject(s)
Carcinoma, Adenosquamous , Laryngeal Neoplasms , Adult , Carcinoma, Adenosquamous/pathology , Humans , Laryngeal Neoplasms/pathology , MaleABSTRACT
We molecular-cloned a novel 80-kDa human glycosyl-phosphatidyl inositol (GPI)-anchored protein, designated GPI-80, that may regulate neutrophil extravasation. To identify the possible role of GPI-80 in vivo, we examined the immunohistochemical localization of GPI-80 in various human tissues. Our data show that GPI-80 is mainly located in polymorphonuclear leukocytes (PMNs), endothelial cells of the vessels, parietal cells and mucous neck cells of the stomach, goblet cells of the jejunum, and alveolar macrophages of the lung. The pathomechanisms of these positive findings in the gastric glands and the intestinal glands are not well elucidated and further studies will be needed.
