title: Insights from HuR biology point to potential improvement for second-line ovarian cancer therapy.
abstract: This retrospective study aimed to investigate the role that an RNA-binding protein, HuR, plays in the response of high-grade serous ovarian tumors to chemotherapeutics. We immunohistochemically stained sections of 31 surgically-debulked chemo-naïve ovarian tumors for HuR and scored the degree of HuR cytoplasmic staining. We found no correlation between HuR intracellular localization in tumor sections and progression free survival (PFS) of these patients, 29 of whom underwent second-line gemcitabine/platin combination therapy for recurrent disease. Ribonucleoprotein immunoprecipitation (RNP-IP) analysis of ovarian cancer cells in culture showed that cytoplasmic HuR increases deoxycytidine kinase (dCK), a metabolic enzyme that activates gemcitabine. The effects of carboplatin treatment on HuR and WEE1 (a mitotic inhibitor) expression, and on cell cycle kinetics, were also examined. Treatment of ovarian cancer cells with carboplatin results in increased HuR cytoplasmic expression and elevated WEE1 expression, arresting cell cycle G2/M transition. This may explain why HuR cytoplasmic localization in chemo-naïve tumors is not predictive of therapeutic response and PFS following second-line gemcitabine/platin combination therapy. These results suggest treatment of recurrent ovarian tumors with a combination of gemcitabine, carboplatin, and a WEE1 inhibitor may be potentially advantageous as compared to current clinical practices.
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19086, USA.|Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Yu-Hung
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19086, USA.
authors.forename: Weidan
authors.initials: W
authors.lastname: Peng
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19086, USA.
authors.forename: Narumi
authors.initials: N
authors.lastname: Furuuchi
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19086, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: DuHadaway
authors.affiliation: Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Masaya
authors.initials: M
authors.lastname: Jimbo
authors.affiliation: Main Line Gynecologic Oncology, Lankenau Medical Center, Wynnewood, PA 19096, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pirritano
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19086, USA.|Main Line Gynecologic Oncology, Lankenau Medical Center, Wynnewood, PA 19096, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Dunton
authors.affiliation: Main Line Health Laboratories, Lankenau Medical Center, Wynnewood, PA 19096, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Daum
authors.affiliation: Division of Biostatistics, Thomas Jefferson University, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Leiby
authors.affiliation: Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Brody
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19086, USA.|Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Sawicki
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D003842:Deoxycytidine Kinase / Q000378:metabolism; D000067780:ELAV-Like Protein 1 / Q000378:metabolism*; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009687:Nuclear Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012189:Retrospective Studies; D000093542:Gemcitabine
chemical_list: D018797:Cell Cycle Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D009687:Nuclear Proteins; D003841:Deoxycytidine; D016190:Carboplatin; D003842:Deoxycytidine Kinase; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D000093542:Gemcitabine
keywords: HuR; WEE1; carboplatin; gemcitabine; ovarian cancer