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: 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, Janet A Sawicki
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 16 Pg. 21812-24 (Apr 19 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26943573 (Publication Type: Journal Article)

Chemical References

• Cell Cycle Proteins
• ELAV-Like Protein 1
• ELAVL1 protein, human
• Nuclear Proteins
• Deoxycytidine
• Carboplatin
• Deoxycytidine Kinase
• Protein-Tyrosine Kinases
• WEE1 protein, human
• Gemcitabine

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carboplatin (administration & dosage)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cytoplasm (metabolism)
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Deoxycytidine Kinase (metabolism)
• ELAV-Like Protein 1 (metabolism)
• Female
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Kaplan-Meier Estimate
• Middle Aged
• Neoplasm Recurrence, Local
• Nuclear Proteins (metabolism)
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Protein Transport (drug effects)
• Protein-Tyrosine Kinases (metabolism)
• Retrospective Studies
• Gemcitabine