The Role of HuR in Gemcitabine Efficacy in Ovarian Cancer
W Rizzo, R Gogoi, C Constantino, J Sawicki, J Brody, A Witkiewicz. Thomas Jefferson University Hospital, Philadelphia, PA; Lankenau Institute for Medical Research, Wynnewood, PA
Background: Ovarian cancer recurs in 50% of women who respond to first line chemotherapy. In patients with platinum-sensitive disease, standard second line chemotherapy agents include gemcitabine (GCB) in combination with platinum. Most second line agents however have only a 15-20% efficacy. The vast majority of patients eventually succumb to the disease. We recently demonstrated that HuR, a stress response protein, is a key mediator of GCB sensitivity through its ability to enhance translation of the drug metabolizing enzyme, deoxycytidine kinase (dCK). In pancreatic carcinoma patients treated with GCB, we reported a 7-fold increased mortality risk in patients with low cytoplasmic HuR levels as compared to those with elevated cytoplamic HuR levels. Thus, the present study investigated the cytoplasmic expression of HuR in ovarian carcinomas and its correlation with response to GCB-based therapy.
Design: Immunohistochemistochemistry for HuR (SCBT, Santa Cruz, CA) was performed on 19 cases of ovarian carcinoma (15 papillary serous, 2 clear cell, and 2 carcinosarcomas). All patients received GCB as part of their second line chemotherapy. Cytoplasmic and nuclear HuR expression was scored as low (< 30% cells staining) or high (>30% of cells staining). Associations between clinicopathologic variables and protein expression were evaluated using a chi-square test. Survival was calculated using the Kaplan–Meier method. Utilizing an RNP-immunoprecipatation assay, we checked the association of deoxycytidine kinase mRNA with HuR in an ovarian cancer cell line, A2780, after GCB treatment. Whether HuR translocated to cytoplasm after GCB treatment in ovarian cancer cells was examined by immunofluoresence.
Results: Median survival was 27 months with low cytoplasmic HuR and 45 months with high HuR tumors (p=0.0081). Abundant cytoplasmic HuR was associated with more advanced disease. An increase in the association of HuR protein bound to dCK mRNA was observed in ovarian cancer cells treated with GCB and HuR translocated to the cytoplasm after exposure to GCM.
Conclusions: Cytoplasmic HuR levels were found to predict GCB response in ovarian carcinoma. This work points to HuR as the regulator of dCK, the key metabolic enzyme of GCB. Thus, our data support the hypothesis that HuR is a key regulator and predictor of GCB efficacy in ovarian cancer.
Category: Gynecologic & Obstetrics
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 169, Wednesday Afternoon