title: Comparative proteomic analysis of paclitaxel sensitive A2780 epithelial ovarian cancer cell line and its resistant counterpart A2780TC1 by 2D-DIGE: the role of ERp57.
abstract: Epithelial ovarian cancer is the leading cause of gynecological cancer mortality. Despite good response to surgery and initial chemotherapy, chemoresistance occurrence represents a major obstacle to a successful therapy. To better understand biological mechanisms at the basis of paclitaxel resistance, a comparative proteomic approach based on DIGE coupled with mass spectrometry (MALDI-TOF and LC-MS/MS) was applied to the human epithelial ovarian cancer cell lines A2780 and its paclitaxel resistant counterpart A2780TC1. Most of the differentially expressed proteins between the two cell lines belong to the class of stress response (29%), metabolism (21%), and cell cycle and apoptosis (17%). We focused on proteins which were most strongly modulated by paclitaxel resistance and in particular on the disulphide isomerase ERp57, which may represent a chemoresistance biomarker. ERp57 was found to interact with class III beta-tubulin (TUBB3), involved in paclitaxel resistance in ovarian and other cancers. Moreover, we demonstrated a novel localization of this protein in cytoskeleton and described that ERp57/TUBB3 interaction occurs also in the nuclear compartment and in association with a multimeric complex formed by nucleolin, nucleophosmin, hnRNPK, and mortalin. Our data suggest that ERp57 plays an important role in chemoresistance mechanisms in ovarian cancer by modulating the attachment of microtubules to chromosomes following paclitaxel treatment through its interaction with TUBB3.
authors.affiliation: Department of Oncology, "RE ARTU" Laboratory of Analytical Techniques and Proteomics, "John Paul II" Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Cicchillitti
authors.forename: Michela
authors.initials: M
authors.lastname: Di Michele
authors.forename: Andrea
authors.initials: A
authors.lastname: Urbani
authors.forename: Cristiano
authors.initials: C
authors.lastname: Ferlini
authors.forename: Maria Benedetta
authors.initials: MB
authors.lastname: Donat
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.forename: Domenico
authors.initials: D
authors.lastname: Rotilio
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D015180:Electrophoresis, Gel, Two-Dimensional; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D013058:Mass Spectrometry; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D011485:Protein Binding; D019704:Protein Disulfide-Isomerases / Q000502:physiology*; D020543:Proteome / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D020543:Proteome; C498585:TUBB3 protein, human; D014404:Tubulin; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human; D017239:Paclitaxel