Insights from HuR biology point to potential improvement for second-line ovarian cancer therapy

// Yu-Hung Huang 1, 2 , Weidan Peng 1 , Narumi Furuuchi 1 , James B. DuHadaway 1 , Masaya Jimbo 6 , Andrea Pirritano 3 , Charles J. Dunton 1, 3 , Gary S. Daum 4 , Benjamin E. Leiby 5, 7 , Jonathan R. Brody 6, 7 , Janet A. Sawicki 1, 7 1 Lankenau Institute for Medical Research, Wynnewood, PA 19086, USA 2 Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19129, USA 3 Main Line Gynecologic Oncology, Lankenau Medical Center, Wynnewood, PA 19096, USA 4 Main Line Health Laboratories, Lankenau Medical Center, Wynnewood, PA 19096, USA 5 Division of Biostatistics, Thomas Jefferson University, Philadelphia, PA 19107, USA 6 Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA 7 Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA Correspondence to: Janet A. Sawicki, e-mail: sawickij@mlhs.org Keywords: HuR, ovarian cancer, gemcitabine, carboplatin, WEE1 Received: January 12, 2016      Accepted: February 21, 2016      Published: March 02, 2016 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-naive 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-naive 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.