Role of tumor necrosis factor-α and TRAIL in high-dose radiation-induced bystander signaling in lung adenocarcinoma

Mohammed M. Shareef, Nuan Cui, Ravshan Burikhanov, Seema Gupta, Sabapathi Satishkumar, Shahin Shajahan, Mohammed Mohiuddin, Vivek M. Rangnekar, Mansoor M. Ahmed

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Abstract

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-α (TNF-α) was observed in A549 cells after IR/RCM exposure, and the survival was reversed with neutralizing antibody against TNF-α. In H460 cells, significant release of TNF-related apoptosis inducing ligand (TRAIL), but not TNF-α, was observed in response to IR, RCM exposure, or RCM + 2Gy, and neutralizing antibody against TRAIL diminished clonogenic inhibition. Mechanistically, TNF-α present in RCM of A549 was found to mediate nuclear factor-κB (NF-κB) 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-α. These findings show that the reduced bystander response in A549 cells is due to activation of NF-κB signaling by TNF-α, whereas enhanced response to IR-induced bystander signaling in H460 cells was due to release of TRAIL associated with nuclear translocation of PAR-4.

Original languageEnglish (US)
Pages (from-to)11811-11820
Number of pages10
JournalCancer Research
Volume67
Issue number24
DOIs
StatePublished - Dec 15 2007

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Shareef, M. M., Cui, N., Burikhanov, R., Gupta, S., Satishkumar, S., Shajahan, S., Mohiuddin, M., Rangnekar, V. M., & Ahmed, M. M. (2007). Role of tumor necrosis factor-α and TRAIL in high-dose radiation-induced bystander signaling in lung adenocarcinoma. Cancer Research, 67(24), 11811-11820. https://doi.org/10.1158/0008-5472.CAN-07-0722