Oncogenic potential of truncated RXR? during colitis-associated colorectal tumorigenesis by promoting IL-6-STAT3 signaling.

Retinoid X receptor-alpha (RXR?) is a potent regulator of inflammatory responses; however, its therapeutic potential for inflammatory cancer remains to be explored. We previously discovered that RXR? is abnormally cleaved in tumor cells and tissues, producing a truncated RXR? (tRXR?). Here, we show that transgenic expression of tRXR? in mice ...
accelerates the development of colitis-associated colon cancer (CAC). The tumorigenic effect of tRXR? 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 tRXR? and TRAF6 in the cytoplasm of macrophages, leading to TRAF6 ubiquitination and subsequent activation of the NF-?B inflammatory pathway. K-80003, a tRXR? modulator derived from nonsteroidal anti-inflammatory drug (NSAID) sulindac, suppresses the growth of tRXR?-mediated colorectal tumor by inhibiting the NF-?B-IL-6-STAT3 signaling cascade. These results provide new insight into tRXR? action and identify a promising tRXR? ligand for treating CAC.
Mesh Terms:
Animals, Carcinogenesis, Colitis, Colitis, Ulcerative, Colon, Colorectal Neoplasms, Culture Media, Conditioned, Disease Models, Animal, HCT116 Cells, Humans, Inflammation, Interleukin-6, Macrophages, Mice, NF-kappa B, Retinoid X Receptor alpha, STAT3 Transcription Factor, Signal Transduction, Sulindac, TNF Receptor-Associated Factor 6
Nat Commun
Date: Dec. 01, 2018
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