HuR is a RNA-binding protein that post-transcriptionally regulates genes involved in the normal cellular response to cancer-associated stressors (e.g., DNA damage, nutrient depletion, hypoxia, and therapeutic agents). When triggered by stress, HuR translocates from the nucleus to the cytoplasm where it potently influences translation of key tumor promoting mRNAs by mRNA stabilization and direct facilitation of translation. Previously, it has been shown that HuR expression is a prognostic marker in ovarian cancers. Thus, we tested the effects of manipulating HuR expression levels on ovarian tumor growth characteristics and tested the hypothesis that silencing HuR through delivery of an HuR siRNA would be effective in suppressing the growth of ovarian tumors. Following treatment of A2780 ovarian cancer cells in culture with an adenovirus containing the HuR coding sequence, HuR expression was increased by ∼40% above control cells as determined by qRT-PCR. When these cells were plated in soft agar, the Adeno-HuR-treated cells markedly enhanced anchorage independent growth properties compared to control cells treated with an Adeno-GFP virus. When OvCAR-3 xenografts in nude mice were injected with lipidoid-siHuR formulated nanoparticles (2 injections/wk, 7 mg/kg/injection), HuR expression was reduced by 80% as determined by immunoblot analysis of resected tumors, and tumor growth was suppressed 2.6-fold after 3 weeks compared to control tumors (siLuciferase- and PBS-treated) (p = 0.0004). After 4 weeks of treatment, all control mice were sacrificed due to large tumor size. siHuR-treated mice continued to receive 2 injections/week for an additional 4 weeks during which time tumor size was maintained at 4-5X the baseline size. In our patient cohort, we also detected HuR activation (i.e., cytoplasmic HuR positivity) in twenty-four of thirty-four patients (71%), providing evidence that the majority of patients have activated HuR. Mechanistically, in A2780 ovarian cancer cells, we detected HuR binding to tumor-promoting target mRNAs including dCK, DR5, and HuR itself. These data provide evidence that silencing HuR, even as a monotherapeutic strategy, may be a promising therapeutic approach for the treatment of ovarian cancer. Studies combining HuR inhibition with other chemotherapies (including gemcitabine), and studies exploring targeting strategies, are ongoing. This work was supported by the Marsha Rivkin Center for Ovarian Cancer Research.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5630. doi:1538-7445.AM2012-5630