Targeting integrins and PI3K/Akt-mediated signal transduction pathways enhances radiation-induced anti-angiogenesis

Shoucheng Ning, Zhijian Chen, Amie Dirks, Bryan Husbeck, Mark Hsu, Barbara Bedogni, Melony O'Neill, Marianne Broome Powell, Susan J. Knox

Research output: Contribution to journalArticle

22 Scopus citations

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 ανβ3 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 signal-ing transduction pathways involved in tumor angiogenesis and enhanced radiation-induced effects on vascular endothelial cells.

Original languageEnglish (US)
Pages (from-to)125-133
Number of pages9
JournalRadiation research
Volume168
Issue number1
DOIs
StatePublished - Jul 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biophysics
  • Radiation
  • Radiology Nuclear Medicine and imaging

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    Ning, S., Chen, Z., Dirks, A., Husbeck, B., Hsu, M., Bedogni, B., O'Neill, M., Powell, M. B., & Knox, S. J. (2007). Targeting integrins and PI3K/Akt-mediated signal transduction pathways enhances radiation-induced anti-angiogenesis. Radiation research, 168(1), 125-133. https://doi.org/10.1667/RR0829.1