title: Inter- and intra-cellular mechanism of NF-kB-dependent survival advantage and clonal expansion of radio-resistant cancer cells.
abstract: Understanding the underlying mechanism by which cancer cells acquire resistance to radiation and favorably selected for its clonal expansion will provide molecular insight into tumor recurrence at the treatment site. In the present study, we investigated the molecular mechanisms prompted in MCF-7 breast cancer cells in response to clinical radiation and the associated coordination of intra- and inter-cellular signaling that orchestrate radio-resistance and tumor relapse/recurrence. Our findings showed that 2 or 10Gy of137Cs γ-rays at a dose rate of 1.03Gy/min trigger the activation of nuclear factor kappa B (NF-κB), its DNA-binding activity and recycles its own transcription. NF-κB DNA-binding kinetic analysis demonstrated both sustained and dual phase NF-κB activation with radiation. Gene manipulation approach revealed that radiation triggered NF-κB-mediated TNF-α transcriptional activity. TNF-α blocking approach confirmed that the de novo synthesis and secretion of TNF-α serves as a pre-requisite for the second phase of NF-κB activation and sustained maintenance. Radiation-associated NF-κB-dependent secretion of TNF-α from irradiated cells, in parallel, activates NF-κB in the non-targeted un-irradiated bystander cells. Together, these findings demonstrated that radiation-triggered NF-κB-dependent TNFα secretion is critical for self-sustenance of NF-κB (through autocrine positive feedback signaling) and for coordinating bystander response (through inter-cellular paracrine mechanism) after radiation exposure. Further, the data suggest that this self-sustained NF-κB in the irradiated cells determines radio-resistance, survival advantage and clonal expansion of the tumor cells at the treatment site. Parallel maintenance of NF-ΚB-TNF-α-NF-κB feedback-cycle in the un-irradiated non-targeted bystander cells initiates supportive mechanism for the promotion and progression of surviving tumor cells. Intervening this molecular pathway would help us to achieve disease-free cancer survivors.
authors.affiliation: Department of Pathology, University of Texas Health Science Center, San Antonio, TX, 78229, USA; Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450001, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Aravindan
authors.affiliation: Department of Pharmacology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan, 450001, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Pathology, University of Texas Health Science Center, San Antonio, TX, 78229, USA. Electronic address: natarajan@uthscsa.edu.
authors.forename: Mohan
authors.initials: M
authors.lastname: Natarajan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D024201:Bystander Effect / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002999:Clone Cells; D004247:DNA / Q000378:metabolism; D005260:Female; D005720:Gamma Rays; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011836:Radiation Tolerance / Q000528:radiation effects; D015533:Transcriptional Activation / Q000235:genetics / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D004247:DNA
keywords: Breast cancer; Feedback signaling; Non-targeted effect; Radiotherapy; Tumor recurrence