Related Experiment Video
Updated: May 31, 2026
07:53
Visualization and Quantitative Analysis of Genotoxin-Induced PARP1/PARP2 Activation in Cells Using a Fluorescent Fusion Protein-Based Reporter
Published on: April 17, 2026
NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699
J E Hunter1, E Willmore, J A E Irving
1Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Tyneside, UK.
Oncogene
|June 28, 2011
Summary
Poly(ADP-ribose) polymerase-1 (PARP-1) inhibition radio-sensitizes cancer cells by blocking nuclear factor (NF)-κB activation, independent of DNA repair. This suggests PARP-1 inhibitors can overcome NF-κB-mediated therapeutic resistance.
Area of Science:
- Molecular Biology
- Cancer Research
- Radiation Oncology
Background:
- Nuclear factor (NF)-κB is a transcription factor regulating proliferation and apoptosis, with aberrant activity linked to cancer and therapeutic resistance.
- Poly(ADP-ribose) polymerase-1 (PARP-1) is involved in DNA strand break repair and acts as a transcriptional co-regulator.
Purpose of the Study:
- To investigate the role of PARP-1 in NF-κB activation and its impact on cancer cell response to ionizing radiation (IR).
- To determine if PARP-1 inhibition can overcome NF-κB-mediated therapeutic resistance.
Main Methods:
- Utilized p65 small interfering RNA (siRNA), PARP siRNA, and the PARP-1 inhibitor AG-014699.
- Assessed cell survival and apoptosis following ionizing radiation (IR) exposure.
- Investigated single-strand break (SSB) repair kinetics and NF-κB p65 DNA binding.
Main Results:
- PARP-1 inhibition (using siRNA or AG-014699) radio-sensitized wild-type cells but not NF-κB p65 knockout cells, indicating PARP-1's role in NF-κB-mediated survival.
- Radio-sensitization by AG-014699 was independent of SSB repair inhibition, suggesting downstream effects on NF-κB activation.
- PARP-1 catalytic activity was crucial for IR-induced NF-κB activation, while PARP-1 protein alone sufficed for tumor necrosis factor-α (TNF-α) activation.
Conclusions:
- PARP-1 inhibition overcomes NF-κB-mediated radio-resistance by inhibiting NF-κB activation, not by impairing SSB repair.
- Targeting DNA damage-activated NF-κB with PARP-1 inhibitors like AG-014699 may offer a strategy to overcome therapeutic resistance with reduced toxicity.
- PARP-1 inhibitors show potential in treating a broader spectrum of cancers by addressing NF-κB-driven resistance mechanisms.
Related Concept Videos
02:26NF-κB-dependent Signaling Pathway
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
02:26NF-kB-dependent Signaling Pathway
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
01:31Transducer Mechanism: Nuclear Receptors
Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
02:04Co-activators and Co-repressors
Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
01:38Nucleotide Excision Repair
DNA Distortion and Damage
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
01:08Nucleotide Excision Repair
Overview