Oncogenic potential of truncated RXRα during colitis-associated colorectal tumorigenesis by promoting IL-6-STAT3 signaling
Open Access
- 1 April 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 10 (1), 1-15
- https://doi.org/10.1038/s41467-019-09375-8
Abstract
Retinoid X receptor-alpha (RXRα) is a potent regulator of inflammatory responses; however, its therapeutic potential for inflammatory cancer remains to be explored. We previously discovered that RXRα is abnormally cleaved in tumor cells and tissues, producing a truncated RXRα (tRXRα). Here, we show that transgenic expression of tRXRα in mice accelerates the development of colitis-associated colon cancer (CAC). The tumorigenic effect of tRXRα is primarily dependent on its expression in myeloid cells, which results in interleukin-6 (IL-6) induction and STAT3 activation. Mechanistic studies reveal an extensive interaction between tRXRα and TRAF6 in the cytoplasm of macrophages, leading to TRAF6 ubiquitination and subsequent activation of the NF-κB inflammatory pathway. K-80003, a tRXRα modulator derived from nonsteroidal anti-inflammatory drug (NSAID) sulindac, suppresses the growth of tRXRα-mediated colorectal tumor by inhibiting the NF-κB-IL-6-STAT3 signaling cascade. These results provide new insight into tRXRα action and identify a promising tRXRα ligand for treating CAC.This publication has 72 references indexed in Scilit:
- Ubiquitination in signaling to and activation of IKKImmunological Reviews, 2012
- TRAF6 is an amplified oncogene bridging the RAS and NF-κB pathways in human lung cancerJCI Insight, 2011
- NSAID Sulindac and Its Analog Bind RXRα and Inhibit RXRα-Dependent AKT SignalingCancer Cell, 2010
- Retinoid X receptor α controls innate inflammatory responses through the up-regulation of chemokine expressionProceedings of the National Academy of Sciences of the United States of America, 2010
- Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statementThe Lancet Oncology, 2009
- Glycogen synthase kinase 3: more than a namesakeBritish Journal of Pharmacology, 2009
- IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated CancerCancer Cell, 2009
- Cancer-related inflammationNature, 2008
- Synergistic effects of RXR and PPAR ligands to inhibit growth in human colon cancer cells phosphorylated RXR is a critical target for colon cancer managementGut, 2007
- Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancerNature Reviews Cancer, 2007