Abstract
The malignant potential of Non-Small Cell Lung Cancer (NSCLC) is dependent on cellular processes that promote metastasis. F-actin organization is central to cell migration, invasion, adhesion and angiogenesis, 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 relevant for controlling metastasis. We previously reported the role of polyisoprenylated cysteinyl amide inhibitors (PCAIs) as potential inhibitors of cancers with hyperactive small GTPases. In this report, we investigate the potential role of PCAIs against NSCLC cells 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 for 24 h caused at least a 66% drop in the levels of Rac1, Cdc42, and RhoA and a 38% drop in F-actin intensity at the cell membrane. 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, a non-farnesylated analog, does not elicit similar effects on F-actin assembly and organization. Our findings indicate that PCAIs disrupt F-actin assembly and organization to suppress cell motility and invasion. The PCAIs may be an effective therapy option for NSCLC metastasis and invasion control.
Highlights
Lung Cancer remains the leading cause of cancerrelated deaths in both men and women in the United States [1]
We investigate the role of polyisoprenylated cysteinyl amide inhibitors (PCAIs) on Rho localization, lamellipodia and filopodia formation, F-actin assembly, cell morphology on Non-Small Cell Lung Cancer (NSCLC) migration and invasion
Our results demonstrate that micro-molar concentrations of PCAIs diminish Rho protein levels and an F-actin-binding protein from the plasma membrane in a time-dependent manner; disrupt filopodia and lamellipodia formation in a time-dependent manner; disrupt F-actin assembly, promote cell rounding, and inhibit 2D and 3D NSCLC migration and invasion
Summary
Lung Cancer remains the leading cause of cancerrelated deaths in both men and women in the United States [1]. About 85% of all lung cancer cases are of the non-small cell lung cancer (NSCLC) histological type [2]. NSCLC accounts for the majority of lung cancer deaths because of its metastatic potential [1]. The Rho proteins are ubiquitously expressed in most cell and tissue types. These proteins are intricately involved in the organization and assembly of the F-actin cytoskeleton and regulate cellular processes of adhesion, migration and invasion [4]. These cellular processes are commonly dysregulated during cancer development and progression to drive tumor metastasis and invasion
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