Abstract 4356: Tumor suppressive miRNA-145 inhibits IGF-1 and cell viability in prostate cancer cells

Abstract

Abstract Castrate resistant prostate cancer that metastasizes (mCRPC) to the bone is the cause of most fatalities of prostate cancer (PCa). Interaction of tumor with the bone microenvironment is critical to progression of bone metastases, enhancing cancer cell survival and proliferation. One of the bone microenvironment-induced factors that promotes metastatic growth is IGF-1, the ligand for IGF-1R, a protein tyrosine kinase receptor frequently overexpressed in bone metastases and when overexpressed, correlated with poor prognosis. We have demonstrated that activation of the IGF-1/1R signaling pathway also induces crosstalk, leading to activation of growth factor receptors including c-MET, currently a target for several inhibitors in clinical trial for mCRPC. We have therefore examined new therapeutic strategies that might integrate targeting IGF-1R and c-MET. We focused on miRNA-mediated gene regulation and new delivery strategies for miRNAs that may lead to therapeutic efficacy. Our work delivering miR-34a through chitosan nanoparticles in vivo, demonstrated decreased tumor growth in the bone. miR-34a inhibits c-MET, Axl, and c-MYC, among other gene products important in PCa progression. However, miR-34a is not predicted to target IGF-1/1R pathway. We thus used miRNA target prediction algorithms to identify miRNAs targeting IGF-1/1R pathway. miR-145, a tumor suppressive miRNA, was predicted to bind the 3′UTR of both IGF-1 and IGF-1R. In many cancers including PCa, miR-145 is shown to be downregulated and in PCa its loss is predictive of poor survival. However, whether miR-145 targets the IGF-1/1R signaling axis and therefore decreases PCa cell survival has not been studied. We performed transient transfection of miR-145 in vitro and demonstrated that while IGF-1R was not inhibited, IGF-1 was inhibited at both the protein and mRNA levels. As a result, constitutive phosphorylation of IGF-1R was inhibited, leading to decreased cell viability and G1 arrest. In conclusion, our in vitro work demonstrates for the first time that miR-145 inhibits IGF-1 expression and decreases PCa cell survival. Future studies will determine if miR-145 can be used for in vivo delivery to inhibit growth of prostate cancer cells in the bone. Since, miR-34a and miR-145 can target multiple genes with overlapping and distinct functions that contribute to PCa growth in the bone, we will also determine whether miRNA combination therapy can be used for inhibiting prostate cancer cell growth in vitro and in vivo and potentially overcome de novo resistance due to receptor crosstalk. The goal of our work is to deliver miRs that inhibit critical pathways as a treatment strategy for bone metastatic PCa. Citation Format: Sanchaika Gaur, Gary Gallick. Tumor suppressive miRNA-145 inhibits IGF-1 and cell viability in prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4356. doi:10.1158/1538-7445.AM2014-4356