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.
Highlights
Retinoid X receptor-alpha (RXRα) is a potent regulator of inflammatory responses; its therapeutic potential for inflammatory cancer remains to be explored
The loxP-truncated Retinoid X receptor α (RXRα) (tRXRα) mice were crossed with the CMV-Cre mice expressing Cre recombinase under the control of cytomegalovirus (CMV) promoter to produce transgenic tRXRα mice (Tg-tRXRα) (Supplementary Fig. 1b) that express various levels of tRXRα in all the tissues examined (Supplementary Fig. 1c)
We found that Tg-tRXRα mice lost less body weight than control mice upon AOM/dextran sodium sulfate (DSS) treatment (Fig. 1b), suggesting that tRXRα expression is involved in the proliferation and survival of colonic epithelial cells
Summary
Retinoid X receptor-alpha (RXRα) is a potent regulator of inflammatory responses; its therapeutic potential for inflammatory cancer remains to be explored. 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. To establish the tumorigenic effect of tRXRα in the development of inflammation-associated cancer and the therapeutic potential of targeting tRXRα-mediated inflammatory signaling pathways, we have generated tRXRα transgenic mice. We report our characterization of the tRXRα transgenic mice with respect to its tumorigenic effects in the development of colitis-associated colon cancer (CAC), the underlying molecular mechanism, and the therapeutic significance
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