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

Retinoid X receptor-alpha (RXR alpha) is a potent regulator of inflammatory responses; however, its therapeutic potential for inflammatory cancer remains to be explored. We previously discovered that RXR alpha is abnormally cleaved in tumor cells and tissues, producing a truncated RXR alpha (tRXR alpha). Here, we show that transgenic expression of tRXR alpha in mice accelerates the development of colitis-associated colon cancer (CAC). The tumorigenic effect of tRXR alpha 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 alpha and TRAF6 in the cytoplasm of macrophages, leading to TRAF6 ubiquitination and subsequent activation of the NF-kappa B inflammatory pathway. K-80003, a tRXR alpha modulator derived from nonsteroidal anti-inflammatory drug (NSAID) sulindac, suppresses the growth of tRXRa-mediated colorectal tumor by inhibiting the NF-kappa B-IL-6-STAT3 signaling cascade. These results provide new insight into tRXRa action and identify a promising tRXR alpha ligand for treating CAC.