Biomaterial Database

Identification of a distinctive P-glycoprotein-mediated resistance phenotype in human ovarian carcinoma cells after their in vitro exposure to fractionated X-irradiation. 1994

B T Hill, and R D Whelan, and H C Hurst, and S McClean

Laboratory of Cellular Chemotherapy, Imperial Cancer Research Fund, London, United Kingdom.

BACKGROUND Clinical drug resistance is recognized in patients previously treated with radiotherapy and after chemotherapy. In vitro exposure of mammalian tumor cells to fractionated X-irradiation also resulted in the expression of drug resistance. Analysis of the resistance phenotype of irradiated Chinese hamster ovary sublines revealed P-glycoprotein overexpression, without any concomitant increase in P-glycoprotein messenger RNA, under posttranslational regulation. This study aimed to determine whether this distinctive resistance phenotype could also be identified in irradiated human tumor cells. METHODS Irradiated sublines established from two human ovarian tumor cell lines, SK-OV-3 and JA-T, which showed resistance to vincristine and to etoposide, were studied. Protein and RNA expression were quantitated by Western and Northern blotting or RNase protection assays. P-glycoprotein turnover was measured after immunoprecipitation of metabolically labelled cells. RESULTS Significant P-glycoprotein overexpression was detected using the C219 and C494 monoclonal antibodies in the two irradiated human ovarian tumor sublines. No concomitant increase in P-glycoprotein messenger RNA was detectable in the SK-OV-3/DXR10 subline, contrasting with the increased message characteristic of vincristine-selected SKVCR sublines. In addition, turnover of P-glycoprotein was significantly reduced in these DXR10 cells when compared with that measured in a vincristine-selected subline. These irradiated sublines showed reduced levels of epidermal growth factor receptors and unchanged levels of topoisomerase II, but they overexpressed c-erbB2 marginally and heat shock protein 27 significantly. These latter elevations in protein levels, however, were associated with concomitant increases in their respective messenger RNAs, implicating regulation at the transcriptional level. CONCLUSIONS Exposure of human ovarian tumor cells to fractionated X-irradiation in vitro resulted in the expression of a distinctive multiple drug resistance phenotype unusually involving posttranslational regulation of P-glycoprotein. Monitoring tumor biopsies for P-glycoprotein-associated drug resistance in patients treated with radiotherapy should evaluate protein levels rather than, or as well as, MDR1 mRNA expression.

UI	MeSH Term	Description	Entries
D008562	Membrane Glycoproteins	Glycoproteins found on the membrane or surface of cells.	Cell Surface Glycoproteins,Surface Glycoproteins,Cell Surface Glycoprotein,Membrane Glycoprotein,Surface Glycoprotein,Glycoprotein, Cell Surface,Glycoprotein, Membrane,Glycoprotein, Surface,Glycoproteins, Cell Surface,Glycoproteins, Membrane,Glycoproteins, Surface,Surface Glycoprotein, Cell,Surface Glycoproteins, Cell
D009363	Neoplasm Proteins	Proteins whose abnormal expression (gain or loss) are associated with the development, growth, or progression of NEOPLASMS. Some neoplasm proteins are tumor antigens (ANTIGENS, NEOPLASM), i.e. they induce an immune reaction to their tumor. Many neoplasm proteins have been characterized and are used as tumor markers (BIOMARKERS, TUMOR) when they are detectable in cells and body fluids as monitors for the presence or growth of tumors. Abnormal expression of ONCOGENE PROTEINS is involved in neoplastic transformation, whereas the loss of expression of TUMOR SUPPRESSOR PROTEINS is involved with the loss of growth control and progression of the neoplasm.	Proteins, Neoplasm
D010051	Ovarian Neoplasms	Tumors or cancer of the OVARY. These neoplasms can be benign or malignant. They are classified according to the tissue of origin, such as the surface EPITHELIUM, the stromal endocrine cells, and the totipotent GERM CELLS.	Cancer of Ovary,Ovarian Cancer,Cancer of the Ovary,Neoplasms, Ovarian,Ovary Cancer,Ovary Neoplasms,Cancer, Ovarian,Cancer, Ovary,Cancers, Ovarian,Cancers, Ovary,Neoplasm, Ovarian,Neoplasm, Ovary,Neoplasms, Ovary,Ovarian Cancers,Ovarian Neoplasm,Ovary Cancers,Ovary Neoplasm
D011506	Proteins	Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.	Gene Products, Protein,Gene Proteins,Protein,Protein Gene Products,Proteins, Gene
D011518	Proto-Oncogene Proteins	Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity.	Cellular Proto-Oncogene Proteins,c-onc Proteins,Proto Oncogene Proteins, Cellular,Proto-Oncogene Products, Cellular,Cellular Proto Oncogene Proteins,Cellular Proto-Oncogene Products,Proto Oncogene Products, Cellular,Proto Oncogene Proteins,Proto-Oncogene Proteins, Cellular,c onc Proteins
D011960	Receptors, Estrogen	Cytoplasmic proteins that bind estrogens and migrate to the nucleus where they regulate DNA transcription. Evaluation of the state of estrogen receptors in breast cancer patients has become clinically important.	Estrogen Receptor,Estrogen Receptors,Estrogen Nuclear Receptor,Estrogen Receptor Type I,Estrogen Receptor Type II,Estrogen Receptors Type I,Estrogen Receptors Type II,Receptor, Estrogen Nuclear,Receptors, Estrogen, Type I,Receptors, Estrogen, Type II,Nuclear Receptor, Estrogen,Receptor, Estrogen
D002352	Carrier Proteins	Proteins that bind or transport specific substances in the blood, within the cell, or across cell membranes.	Binding Proteins,Carrier Protein,Transport Protein,Transport Proteins,Binding Protein,Protein, Carrier,Proteins, Carrier
D002460	Cell Line	Established cell cultures that have the potential to propagate indefinitely.	Cell Lines,Line, Cell,Lines, Cell
D004250	DNA Topoisomerases, Type II	DNA TOPOISOMERASES that catalyze ATP-dependent breakage of both strands of DNA, passage of the unbroken strands through the breaks, and rejoining of the broken strands. These enzymes bring about relaxation of the supercoiled DNA and resolution of a knotted circular DNA duplex.	DNA Topoisomerase (ATP-Hydrolysing),DNA Topoisomerase II,DNA Topoisomerase II alpha,DNA Topoisomerase II beta,DNA Type 2 Topoisomerase,TOP2A Protein,TOP2B Protein,Topoisomerase II,Topoisomerase II alpha,Topoisomerase II beta,Type II DNA Topoisomerase,alpha, Topoisomerase II,beta, Topoisomerase II
D004351	Drug Resistance	Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration.	Resistance, Drug