Oncotarget

Research Papers:

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

Yu-Hung Huang, Weidan Peng, Narumi Furuuchi, James B. DuHadaway, Masaya Jimbo, Andrea Pirritano, Charles J. Dunton, Gary S. Daum, Benjamin E. Leiby, Jonathan R. Brody and Janet A. Sawicki _

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Oncotarget. 2016; 7:21812-21824. https://doi.org/10.18632/oncotarget.7840

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Abstract

Yu-Hung Huang1,2, Weidan Peng1, Narumi Furuuchi1, James B. DuHadaway1, Masaya Jimbo6, Andrea Pirritano3, Charles J. Dunton1,3, Gary S. Daum4, Benjamin E. Leiby5,7, Jonathan R. Brody6,7, Janet A. Sawicki1,7

1Lankenau Institute for Medical Research, Wynnewood, PA 19086, USA

2Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19129, USA

3Main Line Gynecologic Oncology, Lankenau Medical Center, Wynnewood, PA 19096, USA

4Main Line Health Laboratories, Lankenau Medical Center, Wynnewood, PA 19096, USA

5Division of Biostatistics, Thomas Jefferson University, Philadelphia, PA 19107, USA

6Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA

7Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA

Correspondence to:

Janet A. Sawicki, e-mail: [email protected]

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-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.


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