title: Acquired tumor cell radiation resistance at the treatment site is mediated through radiation-orchestrated intercellular communication.
abstract: OBJECTIVE
  Radiation resistance induced in cancer cells that survive after radiation therapy (RT) could be associated with increased radiation protection, limiting the therapeutic benefit of radiation. Herein we investigated the sequential mechanistic molecular orchestration involved in radiation-induced radiation protection in tumor cells.
  
  
  RESULTS
  Radiation, both in the low-dose irradiation (LDIR) range (10, 50, or 100 cGy) or at a higher, challenge dose IR (CDIR), 4 Gy, induced dose-dependent and sustained NFκB-DNA binding activity. However, a robust and consistent increase was seen in CDIR-induced NFκB activity, decreased DNA fragmentation, apoptosis, and cytotoxicity and attenuation of CDIR-inhibited clonal expansion when the cells were primed with LDIR prior to challenge dose. Furthermore, NFκB manipulation studies with small interfering RNA (siRNA) silencing or p50/p65 overexpression unveiled the influence of LDIR-activated NFκB in regulating CDIR-induced DNA fragmentation and apoptosis. LDIR significantly increased the transactivation/translation of the radiation-responsive factors tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), cMYC, and SOD2. Coculture experiments exhibit LDIR-influenced radiation protection and increases in cellular expression, secretion, and activation of radiation-responsive molecules in bystander cells. Individual gene-silencing approach with siRNAs coupled with coculture studies showed the influence of LDIR-modulated TNF-α, IL-1α, cMYC, and SOD2 in induced radiation protection in bystander cells. NFκB inhibition/overexpression studies coupled with coculture experiments demonstrated that TNF-α, IL-1α, cMYC, and SOD2 are selectively regulated by LDIR-induced NFκB.
  
  
  CONCLUSIONS
  Together, these data strongly suggest that scattered LDIR-induced NFκB-dependent TNF-α, IL-1α, cMYC, and SOD2 mediate radiation protection to the subsequent challenge dose in tumor cells.
authors.affiliation: Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Electronic address: naravind@ouhsc.edu.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Aravindan
authors.affiliation: Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Sheeja
authors.initials: S
authors.lastname: Aravindan
authors.affiliation: Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Vijayabaskar
authors.initials: V
authors.lastname: Pandian
authors.affiliation: Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Faizan H
authors.initials: FH
authors.lastname: Khan
authors.affiliation: Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Satish Kumar
authors.initials: SK
authors.lastname: Ramraj
authors.affiliation: Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Praveen
authors.initials: P
authors.lastname: Natt
authors.affiliation: Department of Pathology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Mohan
authors.initials: M
authors.lastname: Natarajan
mesh_terms: D017209:Apoptosis / Q000235:genetics; D024201:Bystander Effect / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034741:RNA, Small Interfering / Q000502:physiology; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000502:physiology* / Q000528:radiation effects; D012542:Scattering, Radiation; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D004273:DNA, Neoplasm; D016898:Interferon-alpha; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D013482:Superoxide Dismutase; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000099156:Superoxide Dismutase 2; C489427:MYC protein, human