title: Sensitization of mesothelioma cells to platinum-based chemotherapy by GSTπ knockdown.
abstract: It is predicted that the incidence of mesothelioma will increase and thus it is important to find new ways to treat this chemoresistant tumor. Glutathione-S-Transferase π (GSTπ) is found at significant levels in mesotheliomas and thus attenuating its intracellular levels may provide a means of sensitizing mesothelioma cells to chemotherapy. GSTπ knockdowns were therefore prepared with shRNA (less off-target effects) employing two cell lines (211H, H2452) that were typed by immunohistochemistry to be of mesothelial origin. The knockdowns exhibited a decrease in both total GST enzyme activity and GSTπ protein levels as well as an increase in both glutathione levels and sensitivity to cis and oxaliplatin. Cisplatin treatment of the knockdowns increased ROS levels significantly (as compared to the parental cells) and produced activation of the JNK/p38 pathways and activating transcription factor (ATF2). The degree of activation and increase in ROS appeared to correlate with the cell line's sensitivity to cisplatin. Treatment with N-Acetyl Cysteine decreased ROS production and JNK/p38 phosphorylation but had minimal affect on ATF2 suggesting a direct interaction of GTPπ with this transcription factor. Oxaliplatin treatment produced only minimal changes in ROS levels and activation of the JNK/p38 pathway. Recently, new methods of siRNA delivery (nanoparticles) have been shown to be effective in decreasing the levels of target proteins in humans including candidate genes involved in drug resistance - thus this approach may have promise in sensitizing cisplatin-resistant tumors to chemotherapy.
authors.affiliation: The Feinstein Institute for Medical Research, NS-LIJ Health System, 350 Community Drive, Manhasset, NY 11030, USA; Department of Pathology and Laboratory Medicine at Staten Island University Hospital, 475 Seaview Avenue, Staten Island, NY 10305, USA. Electronic address: jianli_chen@siuh.edu.
authors.forename: Jianli
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Jefferson Medical College, 132 S. 10th Street, 260E Main, Philadelphia, PA 19107, USA. Electronic address: charalambos.solomides@jefferson.edu.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Solomides
authors.affiliation: The Feinstein Institute for Medical Research, NS-LIJ Health System, 350 Community Drive, Manhasset, NY 11030, USA; Department of Pathology and Laboratory Medicine at Staten Island University Hospital, 475 Seaview Avenue, Staten Island, NY 10305, USA. Electronic address: hsimpkins@siuh.edu.
authors.forename: Henry
authors.initials: H
authors.lastname: Simpkins
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D051698:Activating Transcription Factor 2 / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D051549:Glutathione S-Transferase pi / Q000235:genetics* / Q000378:metabolism; D005982:Glutathione Transferase / Q000187:drug effects; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008654:Mesothelioma / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D009944:Organoplatinum Compounds; D017382:Reactive Oxygen Species; D000077150:Oxaliplatin; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D048670:MAP Kinase Kinase 4; D002945:Cisplatin; D000111:Acetylcysteine
keywords: Cisplatin; Glutathione S Transferase π; Mesothelioma