DNA Damage Response Proteins and XXXX Modulate @entity1421 Growth Factor Release in Response to Low and High LET Ionizing Radiation.

@entity1 @entity522 @entity5 @entity1421 @entity26 @entity3352 @entity9859 @entity2247
Common @entity5 therapies employ chemicals or radiation that damage DNA. @entity5 and normal cells respond to DNA damage by activating complex networks of DNA damage sensor, signal transducer, and effector proteins that arrest cell cycle progression, and repair damaged DNA. If damage is severe enough, the DNA damage response (DDR) triggers programed cell death by apoptosis or other pathways. @entity522 is a protease that is activated upon damage and triggers apoptosis, and production of @entity1421 ( @entity1421 ), a potent growth factor that can enhance growth of surviving @entity5 cells leading to accelerated @entity5 repopulation. Thus, dying @entity5 cells can promote growth of surviving @entity5 cells, a pathway aptly named Phoenix Rising. In the present study, we surveyed Phoenix Rising responses in a variety of normal and established @entity5 cell lines, and in @entity5 cell lines freshly derived from @entity1 . We demonstrate that IR induces a Phoenix Rising response in many, but not all cell lines, and that @entity1421 production generally correlates with enhanced growth of cells that survive irradiation, and of unirradiated cells co-cultured with irradiated cells. We show that @entity1421 production is stimulated by low and high LET ionizing radiation, and can be enhanced or suppressed by inhibitors of key DDR proteins. @entity1421 is produced downstream of @entity522 and the cyclooxygenases @entity9859 and @entity2247 , and we show that the pan @entity9859 -2 inhibitor @entity3352 blocks IR-induced @entity1421 production in the presence or absence of DDR inhibitors. @entity9859 -2 require @entity26 for catalytic activity, and we further show that @entity1421 production is markedly suppressed in cells cultured under low (1%) @entity26 concentration. Thus, Phoenix Rising is most likely to cause repopulation of @entity5 with relatively high @entity26 , but not in @entity5 . This survey lays a foundation for future studies to further define @entity5 responses to radiation and inhibitors of the DDR and Phoenix Rising to enhance the efficacy of radiotherapy with the ultimate goal of precision medicine informed by deep understanding of specific @entity5 responses to radiation and adjunct chemotherapy targeting key factors in the DDR and Phoenix Rising pathways.
