Abstract
Recombinant capsid protein VP1 (rVP1) of foot-and-mouth disease virus binds to integrins to modulate Akt/GSK3-β signaling and suppress migration/invasion and metastasis of cancer cells, but the underlying molecular mechanism is unclear. Here, we showed that the rVP1-mediated inhibition of Akt/GSK3-β signaling and cell migration/invasion was accompanied by downregulation in phosphatidylinositol (3,4,5)-triphosphate (PIP3), integrin-linked kinase (ILK) and IKK/NF-κB signaling as well as suppression of COX-2/PGE2 and MIG-7. Addition of PIP3 or overexpression of ILK reversed the rVP1-induced inhibition of IKK/NF-κB signaling, COX-2 and MIG-7. The rVP1-mediated downregulation of COX-2/PGE2 and MIG-7 led to not only attenuation of epithelial-mesenchymal transition, MMP2 activity and invasion of lung cancer cells in vitro but also decreased tumor growth and metastasis of lung cancer in xenograft mice. Moreover, downregulation of COX-2/PGE2 and MIG-7 significantly prolonged the overall and disease-free survival of lung cancer-bearing mice. These results suggest that rVP1 inhibits cancer invasion/metastasis, partly if not mainly, via downregulating integrin/PI3K/Akt, ILK and IKK/NF-κB signaling to suppress expression of COX-2/PGE2 and MIG-7.
Highlights
Lung cancer is a leading cause of cancer-related death worldwide [1, 2]
To elucidate the mechanism by which Recombinant capsid protein VP1 (rVP1) acts on the integrin β1/Akt signaling of lung cancer cells, we examined the effects of rVP1 on integrin downstream targets, Phosphatidylinositol 3-kinase (PI3K), PIP3, integrin-linked kinase (ILK) and Akt
Overexpression of ILK or NFκB p65 by transfection with pILK or pNFκBp65 blocked the inhibition of COX-2 expression by rVP1 (Figure 3E). These results indicate that rVP1 inhibits integrin/focal adhesion kinase (FAK)/PI3K to decrease the level of PIP3 which in turn modulates ILK level in the lipid rafts to regulate IKK/ NF-κB pathway signaling and COX-2 expression
Summary
Lung cancer is a leading cause of cancer-related death worldwide [1, 2]. Metastasis is the primary cause of lung cancer treatment failure and mortality [1, 3]. Understanding the cellular mediators that contribute to the invasion and metastasis of lung cancer and the development of novel therapeutic agents targeting these mediators are urgently needed. COX-2 is frequently found in early and advanced lung cancer tissues and is associated with poor prognosis [4,5,6,7]. Elevation of tumor COX-2 increases the level of its metabolite prostaglandin E2 (PGE2) that is a ligand of G protein-coupled receptors, such as EP1, EP2, EP3, and EP4.
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