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

ABSTRACT: 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.

SUBMITTER: Ye X 

PROVIDER: S-EPMC6443775 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature