Abstract 914: Ciclopirox olamine (CPX) inhibits breast cancer cell proliferation by blocking the formation of a PEAK1-Src-eIF5a protein complex

Abstract

Abstract The antimycotic drug ciclopirox olamine (CPX) is being evaluated in clinical trials as a re-positioned anti-cancer agent. Although low micromolar concentrations of CPX have been shown to inhibit cell proliferation and solid tumor growth in preclinical models, the mechanism of action remains poorly characterized. In the present study, we demonstrated that CPX treatment potently inhibits cell proliferation and protein expression of the novel tyrosine kinase pseudopodium-enriched atypical kinase 1 (PEAK1) in several breast cancer cell lines, whereas forced overexpression of PEAK1 results in decreased sensitivity to CPX treatment and increased proliferation. PEAK1 protein expression modulates Src kinase activity in proliferating cancer cells and is upregulated in a number of human malignancies, but the mechanisms that regulate its expression have not been characterized (PNAS, 107(24), 10920-5). Here we demonstrate that CPX treatment inhibits the hypusination of eukaryotic translation initiation factor 5a (eIF5a), leading to decreased PEAK1 protein expression and Src kinase activity. siRNA knockdown of eIF5a inhibited PEAK1 expression and Src activity. Likewise, inhibition of Src kinase in cancer cells prevented eIF5a and PEAK1 protein expression, indicating that these proteins tightly regulate one another. Further investigation revealed that in breast cancer cells PEAK1, Src, and eIF5a form a complex which is disassociated by CPX treatment. These findings support a model in which PEAK1 amplification in malignant cells promotes increased Src kinase activity thereby leading to increased eIF5a-mediated PEAK1 protein expression levels. Taken together, these data indicate that CPX has significant potential as a repositioned therapeutic to combat PEAK1 and Src driven human cancers. 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 914. doi:1538-7445.AM2012-914