[5-fluoro-1-(4-isopropylbenzylidene)-2-methylinden-3-yl]acetic-acid and Colitis--Ulcerative

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.

Topics: 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; Signal Transduction; STAT3 Transcription Factor; Sulindac; TNF Receptor-Associated Factor 6