| First Author | Zheng L | Year | 2017 |
| Journal | Mol Cell Biol | Volume | 37 |
| Issue | 15 | PubMed ID | 28533220 |
| Mgi Jnum | J:243911 | Mgi Id | MGI:5912690 |
| Doi | 10.1128/MCB.00149-17 | Citation | Zheng L, et al. (2017) Triptolide-Assisted Phosphorylation of p53 Suppresses Inflammation-Induced NF-kappaB Survival Pathways in Cancer Cells. Mol Cell Biol 37(15) |
| abstractText | 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-kappaB-mediated expression of proliferation and survival genes in cancer cells. Furthermore, triptolide and aspirin induce distinct mechanisms to potentiate each other to block NF-kappaB nuclear localization stimulated by inflammatory cytokines. While aspirin directly inhibits IkappaB kinases (IKKs) to phosphorylate IkappaBalpha for NF-kappaB activation, triptolide does not directly target IKKs or other factors that mediate IKK activation. Instead, it requires p53 to inhibit IkappaBalpha phosphorylation and degradation. Triptolide binds to and activates p38alpha and extracellular signal-regulated kinase 1/2 (ERK1/2), which phosphorylate and stabilize p53. Subsequently, p53 competes with IkappaBalpha for substrate binding to IKKbeta and thereby blocks IkappaBalpha phosphorylation and NF-kappaB nuclear translocation. Inhibition of p38alpha and ERK1/2 or p53 mutations could abolish the inhibitory effects of triptolide on NF-kappaB. Our study defines a new p53-dependent mechanism for blocking NF-kappaB survival pathways in cancer cells. |
