Abstract 1353: Polyisoprenylated cysteinyl amide inhibitors disrupt actin cytoskeleton organization, induce cell rounding, and block invasion of NSCLC

Abstract

Abstract Non-small Cell Lung Cancer (NSCLC) malignancy is dependent on cellular processes that promote metastasis. F-actin organization is central to cell migration, invasion, adhesion and angiogenesis which are all processes involved in metastasis. F-actin remodeling is enhanced by the overexpression and/or hyper-activation of some members of the Rho family of small GTPases. Therefore agents that mitigate hyperactive Rho proteins may be clinically relevant for controlling metastasis. We previously reported the synthesis and characterization of polyisoprenylated cysteinyl amide inhibitors (PCAIs) as potential inhibitors of the cancer phenotype. In this report, we investigate the potential role of PCAIs against NSCLC malignancy and show that as low as 0.5 µM PCAIs significantly inhibit 2D and 3D NCI-H1299 cell migration by 48% and 45%, respectively. PCAIs at 1 µM inhibited 2D and 3D NCI-H1299 cell invasion through Matrigel by 50% and 85%, respectively. Additionally, exposure to 5 µM of the PCAIs, NSL-BA-040 caused a 38% drop in F-actin intensity at the cell membrane 24 h post treatment. Importantly, this drop in F-actin was accompanied by a 73% reduction in the number of filopodia per cell. Interestingly, the polyisoprenyl group of the PCAIs is essential for these effects, as NSL-100, an analog that lacks the farnesyl moiety, does not elicit similar effects on F-actin assembly and organization. Put together, our findings indicate that PCAIs disrupt F-actin assembly and organization to suppress cell motility and invasion and point towards a potential role of PCAIs as effective therapies for NSCLC metastasis and invasion. Citation Format: Elizabeth Ntantie, Jerrine Fletcher, Felix Amissah, Olufisayo O. Salako, Augustine T. Nkembo, Rosemary A. Poku, Nazarius S. Lamango. Polyisoprenylated cysteinyl amide inhibitors disrupt actin cytoskeleton organization, induce cell rounding, and block invasion of NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1353. doi:10.1158/1538-7445.AM2017-1353