title: Identification of ribonucleotide reductase M2 as a potential target for pro-senescence therapy in epithelial ovarian cancer.
abstract: Epithelial ovarian cancer (EOC) is the leading cause of gynecological-related cancer deaths in the United States. There is, therefore, an urgent need to develop novel therapeutic strategies for this devastating disease. Cellular senescence is a state of stable cell growth arrest that acts as an important tumor suppression mechanism. Ribonucleotide reductase M2 (RRM2) plays a key role in regulating the senescence-associated cell growth arrest by controlling biogenesis of 2'-deoxyribonucleoside 5'-triphosphates (dNTPs). The role of RRM2 in EOC remains poorly understood. Here we show that RRM2 is expressed at higher levels in EOCs compared with either normal ovarian surface epithelium (P<0.001) or fallopian tube epithelium (P<0.001). RRM2 expression significantly correlates with the expression of Ki67, a marker of cell proliferation (P<0.001). Moreover, RRM2 expression positively correlates with tumor grade and stage, and high RRM2 expression independently predicts a shorter overall survival in EOC patients (P<0.001). To delineate the functional role of RRM2 in EOC, we knocked down RRM2 expression in a panel of EOC cell lines. Knockdown of RRM2 expression inhibits the growth of human EOC cells. Mechanistically, RRM2 knockdown triggers cellular senescence in these cells. Notably, this correlates with the induction of the DNA damage response, a known mediator of cellular senescence. These data suggest that targeting RRM2 in EOCs by suppressing its activity is a novel pro-senescence therapeutic strategy that has the potential to improve survival of EOC patients.
authors.affiliation: Gene Expression and Regulation Program; The Wistar Institute Cancer Center; The Wistar Institute; Philadelphia, PA USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Aird
authors.affiliation: Gene Expression and Regulation Program; The Wistar Institute Cancer Center; The Wistar Institute; Philadelphia, PA USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Cell and Molecular Biology Graduate Program; School of Medicine; The University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Frances
authors.initials: F
authors.lastname: Xin
authors.affiliation: Medical Gynecological Oncology Program; Dana Farber Cancer Institute; Harvard Medical School; Harvard University; Boston, MA USA.
authors.forename: Panagiotis A
authors.initials: PA
authors.lastname: Konstantinopoulos
authors.affiliation: Gene Expression and Regulation Program; The Wistar Institute Cancer Center; The Wistar Institute; Philadelphia, PA USA.
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D004249:DNA Damage; D004848:Epithelium / Q000201:enzymology; D005187:Fallopian Tubes / Q000201:enzymology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D010053:Ovary / Q000201:enzymology; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D019394:Ki-67 Antigen; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase
keywords: DNA damage response; cell proliferation; cellular senescence; epithelial ovarian cancer; ribonucleotide reductase M2 (RRM2)