Abstract
Abstract Lasonolide A (LSA) was originally identified in a screen for novel antitumor compounds from marine organisms with high and selective cytotoxicity against mesenchymal cancer cells. We recently demonstrated that LSA induces rapid and reversible premature chromosome condensation (PCC) associated with profound epigenetic alterations in different cell types, independently of cyclin-dependent kinases activation. In order to identify cellular targets involved in LSA sensitivity, we used a pool of kinases and phosphatases shRNAs in the human colon carcinoma HCT-116 cell line. Among the genes whose inactivation promotes the survival of LSA-treated cells, we observed an enrichment of genes involved in mitotic functions including Raf1, a well-known serine-threonine kinase regulating cell proliferation and survival. LSA induces the rapid and reversible phosphorylation of Raf1 on Ser338 in a time- and a dose-dependent manner. To establish a causal relationship between LSA-induced PCC and Raf1, we first used siRNA targeting Raf1. Knocking-down Raf1 decreased LSA-induced PCC. Furthermore, mouse embryonic fibroblasts depleted in Raf1 were found resistant to LSA-induced PCC. Our results suggest a novel role of Raf1 in chromatin condensation. They also demonstrate that the target of LSA affects the c-Raf pathway and a novel mechanism of action of LSA as an effective inducer of PCC and potential novel anticancer agent. Citation Format: Yong-Wei Zhang, Rozenn Josse, Arun Ghosh, Ji Luo, Yves Pommier. Lasonolide A-induced premature chromosome condensation is mediated by the proto-oncogene c-Raf (Raf1). [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 2117. doi:10.1158/1538-7445.AM2013-2117 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
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