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Triptolide-Assisted Phosphorylation of p53 Suppresses Inflammation-Induced NF-κB Survival Pathways in Cancer Cells
Li Zheng1, Jia Jia2, Huifang Dai1
1Department of Cancer Genetics and Epigenetics, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA.
Abstract:
Chronic inflammation plays important roles in cancer initiation and progression. Resolving chronic inflammation or blocking inflammatory signal transduction may prevent cancer development. Here, we report that the combined low-dose use of two anti-inflammatory drugs, aspirin and triptolide, reduces spontaneous lung cancer incidence from 70% to 10% in a mouse model. Subsequent studies reveal that such treatment has little effect on resolving chronic inflammatory conditions in the lung, but it significantly blocks the NF-κB-mediated expression of proliferation and survival genes in cancer cells. Furthermore, triptolide and aspirin induce distinct mechanisms to potentiate each other to block NF-κB nuclear localization stimulated by inflammatory cytokines. While aspirin directly inhibits IκB kinases (IKKs) to phosphorylate IκBα for NF-κB activation, triptolide does not directly target IKKs or other factors that mediate IKK activation. Instead, it requires p53 to inhibit IκBα phosphorylation and degradation. Triptolide binds to and activates p38α and extracellular signal-regulated kinase 1/2 (ERK1/2), which phosphorylate and stabilize p53. Subsequently, p53 competes with IκBα for substrate binding to IKKβ and thereby blocks IκBα phosphorylation and NF-κB nuclear translocation. Inhibition of p38α and ERK1/2 or p53 mutations could abolish the inhibitory effects of triptolide on NF-κB. Our study defines a new p53-dependent mechanism for blocking NF-κB survival pathways in cancer cells.
Insights
Low-dose aspirin and triptolide combination therapy significantly reduced lung cancer in mice by blocking NF-κB signaling. This novel approach targets cancer cell survival pathways, offering a potential new strategy for cancer prevention.
Area of Science:
- Oncology
- Inflammation Research
- Molecular Biology
Background:
- Chronic inflammation is a key driver of cancer initiation and progression.
- Targeting inflammatory pathways offers a strategy for cancer prevention.
- Nuclear factor-kappa B (NF-κB) signaling promotes cancer cell proliferation and survival.
Purpose of the Study:
- To investigate the efficacy of combined low-dose aspirin and triptolide in preventing spontaneous lung cancer.
- To elucidate the underlying molecular mechanisms by which this drug combination inhibits cancer development.
Main Methods:
- Utilized a mouse model of spontaneous lung cancer.
- Assessed the impact of aspirin and triptolide on chronic inflammation and NF-κB signaling.
- Investigated the roles of IκB kinases (IKKs), p53, p38α, and extracellular signal-regulated kinase 1/2 (ERK1/2) in the drug mechanism.
Main Results:
- Combined aspirin and triptolide reduced lung cancer incidence from 70% to 10% in mice.
- The treatment did not resolve chronic inflammation but significantly blocked NF-κB-mediated gene expression in cancer cells.
- Aspirin inhibited IKKs, while triptolide activated p38α and ERK1/2, leading to p53-dependent inhibition of NF-κB nuclear translocation.
Conclusions:
- Combined low-dose aspirin and triptolide effectively prevent lung cancer by targeting cancer cell survival pathways.
- A novel p53-dependent mechanism potentiates the inhibition of NF-κB signaling.
- This study defines a new strategy for cancer prevention by modulating inflammatory pathways and cancer cell intrinsic mechanisms.
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