Abstract 3093: AR responsive miR-148a targets p27 and regulates the cell cycle in LNCaP cells.

Abstract

Abstract Prostate cancer is a commonly diagnosed malignancy and represents the second leading cause of cancer-related death in US men. Prostate cancer is initially dependent on androgens for survival and androgen signaling is mediated by the androgen receptor (AR). Due to the androgen dependency of prostate cancer, castration-therapy is a common course of action to combat the progression of this disease. However, almost inevitably, androgen independent prostate cancer later arises for which few strongly effective treatment options exist. In many of these cases, despite the androgen refractive nature of the disease, AR signaling is still necessary for the survival of the cancer but the downstream mechanisms that allow the AR to influence cellular proliferation remain to be fully understood. Further research elucidating these pathways is needed to discover novel therapeutic options for this disease. It has been shown that the AR represses the function of the cyclin dependent kinase inhibitor p27 but the way in which this happens is not completely known and seems to be multi-pronged. Research from Murata et al. (2010) demonstrated that miR-148a is an androgen responsive microRNA. Furthermore, it was shown by Guo et al. (2011) that miR-148a targets p27 in gastric cancer. Here we attempt to link these lines of research and uncover a novel pathway in which the relationship between the AR and p27 is mediated by miR-148a. We validated previous results showing that inhibition of AR signaling leads to an increase in p27 expression at both the protein and mRNA levels in the androgen responsive prostate cancer cell line LNCaP. It was shown that AR inhibition leads to an ∼2 fold decrease in miR-148a expression. Using a microRNA mimic, we demonstrated the ability of miR-148a to target p27 expression at both the protein and mRNA levels. We next showed that the miR-148a mimic can rescue the attenuated androgen signaling phenotype by reducing p27 levels and further demonstrate that this treatment leads to positive regulation of the cell cycle. Interestingly, inhibition of function using an antagomir against miR-148a leads to attenuated growth in LNCaPs suggesting a putative therapeutic angle by targeting this pathway. These results demonstrate a novel pathway mediated by the AR in which a miRNA is expressed which potentiates the cell cycle by targeting p27. Citation Format: Alan Lombard, Steve Libertini, Maria Mudryj. AR responsive miR-148a targets p27 and regulates the cell cycle in LNCaP cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3093. doi:10.1158/1538-7445.AM2013-3093 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.