Polyisoprenylated cysteinyl amide inhibitors disrupt actin cytoskeleton organization, induce cell rounding and block migration of non-small cell lung cancer

Elizabeth Ntantie, Jerrine Fletcher, Felix Amissah, Olufisayo O. Salako, Augustine T. Nkembo, Rosemary A. Poku, Offiong Ikpatt, Nazarius S. Lamango

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)31726-31744
Number of pages19
JournalOncotarget
Volume8
Issue number19
DOIs
StatePublished - 2017

Fingerprint

Actin Cytoskeleton
Amides
Non-Small Cell Lung Carcinoma
Organizations
Actins
Neoplasm Metastasis
Cell Movement
Monomeric GTP-Binding Proteins
Pseudopodia
Cell Membrane
Neoplasms
Proteins

Keywords

  • Cell invasion
  • Filopodia
  • Lamellipodia
  • PCAIs
  • RhoA

ASJC Scopus subject areas

  • Oncology

Cite this

Polyisoprenylated cysteinyl amide inhibitors disrupt actin cytoskeleton organization, induce cell rounding and block migration of non-small cell lung cancer. / Ntantie, Elizabeth; Fletcher, Jerrine; Amissah, Felix; Salako, Olufisayo O.; Nkembo, Augustine T.; Poku, Rosemary A.; Ikpatt, Offiong; Lamango, Nazarius S.

In: Oncotarget, Vol. 8, No. 19, 2017, p. 31726-31744.

Research output: Contribution to journalArticle

Ntantie, Elizabeth ; Fletcher, Jerrine ; Amissah, Felix ; Salako, Olufisayo O. ; Nkembo, Augustine T. ; Poku, Rosemary A. ; Ikpatt, Offiong ; Lamango, Nazarius S. / Polyisoprenylated cysteinyl amide inhibitors disrupt actin cytoskeleton organization, induce cell rounding and block migration of non-small cell lung cancer. In: Oncotarget. 2017 ; Vol. 8, No. 19. pp. 31726-31744.
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AU - Salako, Olufisayo O.

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AB - 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.

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