Cytosolic phospholipase A2 regulates viability of irradiated vascular endothelium.
Radiosensitivity of various normal tissues is largely dependent on radiation-triggered signal transduction pathways. Radiation simultaneously initiates distinct signaling from both DNA damage and cell membrane. Specifically, DNA strand breaks initiate cell-cycle delay, strand-break repair or programmed cell death, whereas membrane-derived signaling through phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) enhances cell viability. Here, activation of cytosolic phospholipase A(2) (cPLA(2)) and production of the lipid second-messenger lysophosphatidylcholine were identified as initial events (within 2 min) required for radiation-induced activation of Akt and ERK1/2 in vascular endothelial cells. Inhibition of cPLA(2) significantly enhanced radiation-induced cytotoxicity due to an increased number of multinucleated giant cells and cell cycle-independent accumulation of cyclin B1 within 24-48 h of irradiation. Delayed programmed cell death was detected at 72-96 h after treatment. Endothelial functions were also affected by inhibition of cPLA(2) during irradiation resulting in attenuated cell migration and tubule formation. The role of cPLA(2) in the regulation of radiation-induced activation of Akt and ERK1/2 and cell viability was confirmed using human umbilical vein endothelial cells transfected with shRNA for cPLA(2)alpha and cultured embryonic fibroblasts from cPLA(2)alpha(-/-) mice. In summary, an immediate radiation-induced cPLA(2)-dependent signaling was identified that regulates cell viability and, therefore, represents one of the key regulators of radioresistance of vascular endothelial cells.
Yazlovitskaya
E M
EM
Department of Radiation Oncology, Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN 37232-5671, USA.
Linkous
A G
AG
Thotala
D K
DK
Cuneo
K C
KC
Hallahan
D E
DE
D000818:Animals; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology*; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008244:Lysophosphatidylcholines / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology / Q000528:radiation effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D008244:Lysophosphatidylcholines; D034741:RNA, Small Interfering; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D054513:Group IV Phospholipases A2