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 of 137Cs 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.
journal_name
Cell Signaljournal_title
Cellular signallingauthors
Yu H,Aravindan N,Xu J,Natarajan Mdoi
10.1016/j.cellsig.2017.01.011subject
Has Abstractpub_date
2017-02-01 00:00:00pages
105-111eissn
0898-6568issn
1873-3913pii
S0898-6568(17)30011-6journal_volume
31pub_type
杂志文章abstract::Microglia play a prominent role in the brain's inflammatory response to injury or infection by migrating to affected locations, secreting inflammatory molecules, and phagocytosing damaged tissue. However, because severe or chronic neuroinflammation exacerbates many neurological conditions, controlling microglia action...
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journal_title:Cellular signalling
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journal_title:Cellular signalling
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journal_title:Cellular signalling
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journal_title:Cellular signalling
pub_type: 杂志文章
doi:10.1016/j.cellsig.2008.06.016
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journal_title:Cellular signalling
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doi:10.1016/j.cellsig.2005.06.001
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journal_title:Cellular signalling
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journal_title:Cellular signalling
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journal_title:Cellular signalling
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journal_title:Cellular signalling
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