ABSTRACT
BCL-2 family proteins regulate the mitochondrial apoptotic pathway. BOK, a multidomain BCL-2 family protein, is generally believed to be an adaptor protein similar to BAK and BAX, regulating the mitochondrial permeability transition during apoptosis. Here we report that BOK is a positive regulator of a key enzyme involved in uridine biosynthesis; namely, uridine monophosphate synthetase (UMPS). Our data suggest that BOK expression enhances UMPS activity, cell proliferation, and chemosensitivity. Genetic deletion of Bok results in chemoresistance to 5-fluorouracil (5-FU) in different cell lines and in mice. Conversely, cancer cells and primary tissues that acquire resistance to 5-FU down-regulate BOK expression. Furthermore, we also provide evidence for a role for BOK in nucleotide metabolism and cell cycle regulation. Our results have implications in developing BOK as a biomarker for 5-FU resistance and have the potential for the development of BOK-mimetics for sensitizing 5-FU-resistant cancers.
Subject(s)
Proto-Oncogene Proteins c-bcl-2/metabolism , Uridine/metabolism , Animals , Apoptosis/drug effects , Biomarkers, Tumor/metabolism , Cell Proliferation/drug effects , DNA Damage , Drug Resistance, Neoplasm/drug effects , Fluorouracil/pharmacology , Mammals , Mice , Multienzyme Complexes/metabolism , Orotate Phosphoribosyltransferase/metabolism , Orotidine-5'-Phosphate Decarboxylase/metabolism , Protein Binding/drug effects , Protein Domains , Proto-Oncogene Proteins c-bcl-2/chemistry , Tumor Suppressor Protein p53/metabolismSubject(s)
Biomedical Research , Financial Management , Health Resources/trends , Australia , Biomedical Research/economics , Biomedical Research/standards , Biomedical Research/trends , Financial Management/organization & administration , Financial Management/trends , Health Care Rationing/methods , Health Promotion/organization & administration , Humans , Preventive Medicine/organization & administration , Quality Improvement/organization & administrationABSTRACT
PURPOSE: During cancer surgery, prostaglandin-mediated inflammation may promote and activate micrometastatic disease with a consequent increase in long-term cancer recurrence. Cyclooxygenase-2 inhibitors, known to have anti-proliferative properties, may offset such perioperative perturbation. We investigated the effectiveness of these agents to minimize inflammatory changes during cancer surgery. METHODS: Following ethics approval, 32 patients who were to undergo major intracavity cancer surgery were enrolled in this prospective, randomized, clinical trial. The treatment group received 400 mg celecoxib preoperatively followed by five 200 mg 12-hourly doses. The control group received no anti-inflammatory agents. Inflammatory and immunomodulatory end points were measured serially. The primary end points were the measured plasma and urinary prostaglandin E metabolite (PGEM) levels 48 hours following surgery. Secondary endpoints included interleukin levels, leucocyte profile, and clinical end points. RESULTS: No differences in the 48-hr plasma or urinary PGEM levels were observed between the celecoxib and control groups. Linear mixed modeling, used to accommodate differences in baseline PGEM levels, showed that celecoxib (cf. control) administration lowered plasma PGEM over the entire 48-hr period following surgery (ß-coefficient = -0.38 pg.ml-1; 95% confidence interval: -0.69 to -0.06; P = 0.021). Celecoxib administration also lowered postoperative pain scores. DISCUSSION: Standard dosing of the cyclooxygenase-2 inhibitor celecoxib slightly reduced perioperative cyclooxygenase activity during cancer surgery. Given cyclooxygenase's role in cancer pathways, we recommend dose-finding studies be undertaken before prospective clinical trials are conducted testing the currently unsubstantiated hypothesis that perioperative anti-inflammatory administration improves long-term cancer outcomes. This trial was registered at: Australian New Zealand Clinical Trial Registry: ACTRN12615000041550; www.anzctr.org.au.
