Targeting Invasion Induction as a Therapeutic Strategy for the Treatment of Cancer

Livant, Donna L.

doi:10.2174/156800905774574002

Cited by 17 publications

(20 citation statements)

References 130 publications

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“…The a 5 h 1 integrin interacts with the PHSRN sequence of fibronectin cell-binding domain fragments to stimulate invasion during wound healing (2). Because epithelial cells, fibroblasts, and endothelial cells express the invasion-inhibitory a 4 h 1 integrin as well as a 5 h 1 , fibronectin fragmentation is required for invasion induction (3). Integrins are also very important in cancer progression (4).…”

Section: Introductionmentioning

confidence: 99%

“…18), thereby bringing the catalytic subunit of PI3K to the membrane, where it catalyzes phosphorylation of inositol lipids at the D-3 position to form 3 ¶-phosphorylated phosphoinositides, including phosphatidylinositol-3,4,5-trisphosphate (PIP 3 ). Integrin activation-induced FAK/PI3K association has been shown in both platelets and fibroblasts (19).…”

Section: Introductionmentioning

confidence: 99%

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Role of Focal Adhesion Kinase and Phosphatidylinositol 3′-Kinase in Integrin Fibronectin Receptor-Mediated, Matrix Metalloproteinase-1–Dependent Invasion by Metastatic Prostate Cancer Cells

et al. 2006

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A 5 B 1 Integrin interacts with the PHSRN sequence of plasma fibronectin, causing constitutive invasion by human prostate cancer cells. Inhibition of this process reduces tumorigenesis and prevents metastasis and recurrence. In this study, naturally serum-free basement membranes were used as in vitro invasion substrates. Immunoassays were employed to dissect the roles of focal adhesion kinase (FAK), phosphatidylinositol 3 ¶-kinase (PI3K), and protein kinase CD (PKCD) in A 5 B 1 -mediated, matrix metalloproteinase-1 (MMP-1)-dependent invasion by metastatic human DU 145 prostate cancer cells. We found that a peptide composed of the PHSRN sequence induced rapid FAK phosphorylation at Tyr 397 (Y397), a site whose phosphorylation is associated with kinase activation. The technique of RNA silencing [small interfering RNA (siRNA)] confirmed the role of FAK in PHSRN-induced invasion. PHSRN also induced the association of the p85-regulatory subunit of PI3K with FAK at a time corresponding to FAK phosphorylation and activation, and maximal PI3K activity occurred at this same time. The necessity of PI3K activity in both PHSRN-induced invasion and MMP-1 expression was confirmed by using specific PI3K inhibitors. By employing a specific inhibitor, Rottlerin, and by using siRNA, we also found that PKCD, a PI3K substrate found in focal adhesions, functions in PHSRN-induced invasion. In addition, the induction of MMP-1 in PHSRN-treated DU 145 cells was shown by immunoblotting, and the role of MMP-1 in PHSRNinduced invasion was confirmed by the use of blocking anti-MMP-1 monoclonal antibody. Finally, a close temporal correspondence was observed between PHSRN-induced invasion and PHSRN-induced MMP-1 activity in DU 145 cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of Focal Adhesion Kinase and Phosphatidylinositol 3′-Kinase in Integrin Fibronectin Receptor-Mediated, Matrix Metalloproteinase-1–Dependent Invasion by Metastatic Prostate Cancer Cells

et al. 2006

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“…[20] Briefly, titanium (40 ) and gold (220 ) were evaporated onto glass coverslips using an electron beam evaporator (Thermionics) at a rate of 0.2-0.4 nm s À1 with a pressure of 1.0 10 À6 Torr. Monolayers were formed by immersing these substrates into an ethanolic solution containing a mixture of a symmetric tri(ethylene glycol)-terminated disulfide (EG 3 ) and an asymmetric disulfide with tri(ethylene glycol) and maleimide head groups for 12-16 h at room temperature . The disulfide reagents were used at a concentration of 0.5 mm with the maleimide-terminated group present at relative fractions of 1 % on the surface.…”

Section: Methodsmentioning

confidence: 99%

“…[9,10] These compounds, at micromolar concentrations, were shown to block cell migration, but recent work reported that lower concentrations of these drugs can actually enhance the growth of tumors in vivo by promoting migration and VEGF-mediated angiogenesis. [7] Other recent work has investigated the analogy between tumor angiogenesis and wound healing [3,11] with the finding that the fibronectin-derived Pro-His-SerArg-Asn (PHSRN) peptide can stimulate migration of human kerotinocytes and fibroblasts and accelerate wound healing in obese diabetic mice. [8] Our group [12,13] and others [14] have suggested that PHSRN antagonizes RGD binding, and therefore may accelerate migration by inhibiting the integrinmediated adhesion.…”

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confidence: 99%

“…[2] Inhibitors of the integrin receptor have been explored as reagents that may block cell migration and recent work has advanced a class of soluble RGD peptides as possible therapeutics that display anti-metastatic activity. [3][4][5] But the molecular mechanisms by which these compounds block migration have not been elucidated and have recently been contradicted by work that demonstrates that the soluble antagonists can also promote the migration of tumor cells. [6][7][8] Herein, we use a well-defined model system to assess the influence of soluble inhibitors on cell migration and we show that the integrin antagonists are able to promote the migration of cells.…”

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An Inhibitor of a Cell Adhesion Receptor Stimulates Cell Migration

2010

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The integrins are a family of heterodimeric receptors that play a universal role in mediating the adhesion of cells to the extracellular matrix. As such, the differential interactions of the receptors at the front and back ends of the cell are important in regulating the migration of cells. [1] Approximately one-half of the integrins recognize the canonical RGD motif found in fibronectin, and a significant body of work has shown that model substrates presenting the RGD peptide support the adhesion and migration of cells. [2] Inhibitors of the integrin receptor have been explored as reagents that may block cell migration and recent work has advanced a class of soluble RGD peptides as possible therapeutics that display anti-metastatic activity. [3][4][5] But the molecular mechanisms by which these compounds block migration have not been elucidated and have recently been contradicted by work that demonstrates that the soluble antagonists can also promote the migration of tumor cells. [6][7][8] Herein, we use a well-defined model system to assess the influence of soluble inhibitors on cell migration and we show that the integrin antagonists are able to promote the migration of cells.The RGD-mimetic compounds cilengitide and S36578 were developed as integrin antagonists and are now in early phase clinical trials for cancer therapy. [9,10] These compounds, at micromolar concentrations, were shown to block cell migration, but recent work reported that lower concentrations of these drugs can actually enhance the growth of tumors in vivo by promoting migration and VEGF-mediated angiogenesis. [7] Other recent work has investigated the analogy between tumor angiogenesis and wound healing [3,11] with the finding that the fibronectin-derived Pro-His-SerArg-Asn (PHSRN) peptide can stimulate migration of human kerotinocytes and fibroblasts and accelerate wound healing in obese diabetic mice. [8] Our group [12,13] and others [14] have suggested that PHSRN antagonizes RGD binding, and therefore may accelerate migration by inhibiting the integrinmediated adhesion. Additionally, it has been reported that addition of insulin-like growth factor binding protein (IGFBP-1) which contains the RGD sequence in the cell culture medium increases the migration of CHO cells twofold compared to cells treated with Trp-Gly-Asp (WGD). [6] The literature contains several additional contradictory reports as to the effect of soluble RGD-containing proteins on adhesion and migration. [5,15] Mechanistic studies of the roles of ligand-receptor interactions in cell migration are challenging because it is difficult to control which interactions operate between cell and matrix. This limitation is particularly relevant to in vivo experiments, where a broad range of signals and matrix constituents are present and not always defined. [16] Even in the laboratory, it can be difficult to reproducibly present matrix ligands to a cell in order to obtain reproducible matrix formulations. [5] To address these limitations, we use selfassembled monolayers that presen...

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