Basic Fibroblast Growth Factor Inhibits Radiation-Induced Apoptosis of HUVECs. I. The PI3K/AKT Pathway and Induction of Phosphorylation of BAD

Abstract

Radiation-induced endothelial cell apoptosis is involved in the development of many radiation injuries, including radiation-induced skin ulcers. The proangiogenic growth factors basic fibroblast growth factor (bFGF, NUDT6) and VEGF enhance endothelial cell survival. In the present study, we used primary cultured human umbilical vein endothelial cells (HUVECs) irradiated with (60)Co gamma rays to explore the effects of bFGF on radiation-induced apoptosis of HUVECs and its signaling pathways. We found that bFGF inhibited radiation-induced apoptosis of HUVECs, and that the effect was mediated by the PI3K/AKT pathway. This pathway was activated by exposure of irradiated HUVECs to bFGF, involving phosphorylation of FGFR, PI3K and AKT. The survival-enhancing effect of bFGF was abrogated by wortmannin and LY294002. Transfection of a dominant-negative mutant of AKT completely blocked the anti-apoptosis effect of bFGF in irradiated HUVECs. We also found evidence for the first time that bFGF induced BAD phosphorylation in the gamma-irradiated HUVECs. These results showed that the PI3K/AKT pathway participated in the bFGF-induced modulation of the survival of irradiated HUVECs. Activation of the PI3K/AKT pathway plays an important role in bFGF-induced endothelial cell survival in the treatment of radiation-induced skin ulcers.

Hesperidin Increase Cytotoxic Activity of Doxorubicin on Hela Cell Line Through Cell Cycle Modulation and Apoptotis Induction

“…Hesperidin and doxorubicin show decreasing of Bcl-2 level on HeLa. Hesperidin suppressed TPAstimulated NF-κB translocation into the nucleus through IκB inhibitory signaling pathways and also inhibited TPA-induced AP-1 activity by the inhibitory phosphorylation of p38 kinase and c-Jun N-terminal kinase (JNK) signaling pathways (Lee et al, 2010) and inhibition of PI3K path that eventually spur apoptosis through inhibition of inactivation of Bad (Gu et al, 2004). Increased apoptosis by the combination of hesperidin and doxorubicin via inhibition of NF-κB activation can also occur through inhibition of MAP kinase and PI3K path.…”

Dose-dependent response of tumor vasculature to radiation therapy in combination with Sunitinib depicted by three-dimensional high-frequency power Doppler ultrasound

“…Conventional radiation doses are believed not to activate the ceramide-dependent apoptosis pathway. Basic fibroblast growth factor (bFGF) has been shown to inhibit ceramide-dependent messaging for apoptosis [10,[15][16][17][18][19]. In comparison, epithelial and tumor cells are predominantly damaged through direct or indirect DNA damage, and undergo cell death or senescence only when they have accumulated adequate damage [9,20,21].…”

Silibinin strongly inhibits growth and survival of human endothelial cells via cell cycle arrest and downregulation of survivin, Akt and NF-κB: implications for angioprevention and antiangiogenic therapy

“…Many studies have suggested that activation of Akt pathway including other mitogenic and survival signaling are critical for the growth, survival and migration of endothelial cells (Kim et al, 1993;Qi et al, 1999;Carmeliet, 2002;Chen et al, 2004;Gingis-Velitski et al, 2004;Gu et al, 2004). Nuclear factor kappa B (NF-kB), a hetrodimeric transcription factor, is known to modulate the transcription of genes responsible for the growth and survival as well as inhibition of apoptosis (Baldwin, 1996;Baeuerle and Baltimore, 1996;Levkau et al, 1999;Malyankar et al, 2000;Yamamoto and Gaynor, 2001).…”