title: Cisplatin sensitivity mediated by WEE1 and CHK1 is mediated by miR-155 and the miR-15 family.
abstract: Resistance to platinum-based therapies arises by multiple mechanisms, including by alterations to cell-cycle kinases that mediate G(2)-M phase arrest. In this study, we conducted parallel high-throughput screens for microRNAs (miRNA) that could restore sensitivity to cisplatin-resistant cells, and we screened for kinases targeted by miRNAs that mediated cisplatin resistance. Overexpression of the cell-cycle kinases WEE1 and CHK1 occurred commonly in cisplatin-resistant cells. miRNAs in the miR-15/16/195/424/497 family were found to sensitize cisplatin-resistant cells to apoptosis by targeting WEE1 and CHK1. Loss-of-function and gain-of-function studies showed that miR-15 family members controlled the expression of WEE1 and CHK1. Supporting these results, we found that in the presence of cisplatin altering expression of miR-16 or related genes altered cell cycle distribution. Our findings reveal critical regulation of miRNAs and their cell-cycle-associated kinase targets in mediating resistance to cisplatin.
authors.affiliation: Department of Microbiology and Immunology, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Pouliot
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Chen
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bai
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Guha
authors.forename: Scott E
authors.initials: SE
authors.lastname: Martin
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hall
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D057166:High-Throughput Screening Assays; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C505361:MIRN15 microRNA, human; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D002945:Cisplatin