Targeting Integrins and PI3K/Akt-Mediated Signal Transduction Pathways Enhances Radiation-Induced Anti-angiogenesis

Abstract

The integrins and PI3K/Akt are important mediators of the signal transduction pathways involved in tumor angiogenesis and cell survival after exposure to ionizing radiation. Selective targeting of either integrins or PI3K/Akt can radiosensitize tumors. In this study, we tested the hypothesis that the combined inhibition of integrin alphanubeta3 by cRGD and PI3K/Akt by LY294002 would significantly enhance radiation-induced inhibition of angiogenesis by vascular endothelial cells. Treatment with cRGD inhibited the adhesion and tube formation of human umbilical vein endothelial cells (HUVECs). The inhibitory effect was further increased when cRGD and LY294002 were applied simultaneously. Both radiation and cRGD induced Akt phosphorylation, up-regulated COX2 expression, and increased PGE2 production in HUVECs. Treatment with LY294002 effectively inhibited radiation- and cRGD-induced Akt phosphorylation and up-regulation of COX2 and increased apoptosis of HUVECs. The combined use of cRGD and LY294002 enhanced radiation-induced cell killing. The clonogenic survival of HUVECs was decreased from 34% with 2 Gy radiation to 4% with these agents combined. These results demonstrate that combined use of ionizing radiation, cRGD and LY294002 inhibited multiple signaling transduction pathways involved in tumor angiogenesis and enhanced radiation-induced effects on vascular endothelial cells.

HAb18G/CD147 Promotes Radioresistance in Hepatocellular Carcinoma Cells: A Potential Role for Integrin β1 Signaling

“…PI3K/Akt signaling is well characterized with respect to promoting cell survival and suppressing apoptosis. There is evidence that PI3K pathway inhibition enhances radiation-induced antiangiogenesis and increases tumor radiosensitivity by normalizing the tumor vasculature (38,39). Our data showed that radiation activated FAK-PI3K/Akt signaling.…”

Endothelial cells in the context of brain arteriovenous malformations

“…21 Integrins are key regulators of angiogenesis by controlling signal transduction. 22 In conjunction with other pro-angiogenic factors, they are key to migration, adhesion, proliferation and differentiation of EC. Tumour research has identified two integrins important in tumour angiogenesis, amb3 and amb5, that are highly expressed not only on some tumour cells, but also on neurovascular EC.…”

“…The amb3 signalling that occurs after irradiation can be interrupted by coadministration of the integrin binding cyclic Arg-Gly-Asp (cRGD) peptide; 25 blocking the interaction between amb3 and its natural ligands results in adhesion disruption, detachment of EC from the matrix and increased levels of apoptosis. 22 …”

“…48 Radiation can cause endothelial cell activation, causing over-expression of the proangiogenic and pro-survival factors VEGF, phosphoinositide 3 kinase/protein kinase B (PI3k/Akt), cyclooxygenase 2, and integrin receptors. 22 One of the most common effects of radiation is damage to EC integrity resulting in altered function, including loss of control of vascular tone and blood pressure. A cardiac-based study sought to identify the effect of c-irradiation on mRNA expression of ICAM-1.…”

Anti–αv Integrin Monoclonal Antibody Intetumumab Enhances the Efficacy of Radiation Therapy and Reduces Metastasis of Human Cancer Xenografts in Nude Rats

“…To fully assess the effects of intetumumab on radiation response of tumors and interaction of tumor cells and their microenvironments, we next studied the combined use of intetumumab and fractionated local tumor radiation therapy in nude rats with human cancer xenograft. Based on our previous studies (5,8,9), we hypothesized that intetumumab would potentiate the efficacy of fractionated radiation therapy and inhibit tumor metastasis by blocking the function of adhesion molecules in the microenvironment of potential metastatic sites.…”