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Role of Tumor Necrosis Factor- and TRAIL in High-Dose Radiation–Induced Bystander Signaling in Lung Adenocarcinoma

¹ Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania; ² Department of Radiation Medicine, University of Kentucky, Lexington, Kentucky; ³ Geisinger-Fox Chase Cancer Center, Geisinger Clinic, Wilkes-Barre, Pennsylvania; and ⁴ Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania

Requests for reprints: Mansoor M. Ahmed, Weis Center for Research, Geisinger Clinic, Office 121A, 100 N. Academy Avenue, Danville, PA 17822-2616. Phone: 570-214-3972 or 570-271-8660; Fax: 570-214-9861; E-mail: mmahmed{at}geisinger.edu.

In the present study, ionizing radiation (IR)–induced bystander effects were investigated in two lung cancer cell lines. A549 cells were found to be more resistant to radiation-conditioned medium (RCM) obtained from A549 cells when compared with the H460 exposed to RCM procured from H460 cells. Significant release of tumor necrosis factor- (TNF-) was observed in A549 cells after IR/RCM exposure, and the survival was reversed with neutralizing antibody against TNF-. In H460 cells, significant release of TNF-related apoptosis-inducing ligand (TRAIL), but not TNF-, was observed in response to IR, RCM exposure, or RCM + 2Gy, and neutralizing antibody against TRAIL diminished clonogenic inhibition. Mechanistically, TNF- present in RCM of A549 was found to mediate nuclear factor-B (NF-B) translocation to nucleus, whereas the soluble TRAIL present in RCM of H460 cells mobilized the nuclear translocation of PAR-4 (a proapoptotic protein). Analysis of IR-inducible early growth response-1 (EGR-1) function showed that EGR-1 was functional in A549 cells but not in H460 cells. A significant decrease in RCM-mediated apoptosis was observed in both A549 cells stably expressing small interfering RNA EGR-1 and EGR-1^–/– mouse embryonic fibroblast cells. Thus, the high-dose IR-induced bystander responses in A549 may be dependent on the EGR-1 function and its target gene TNF-. These findings show that the reduced bystander response in A549 cells is due to activation of NF-B signaling by TNF-, whereas enhanced response to IR-induced bystander signaling in H460 cells was due to release of TRAIL associated with nuclear translocation of PAR-4. [Cancer Res 2007;67(24):11811–20]

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