| First Author | Ye X | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 1463 |
| PubMed ID | 30931933 | Mgi Jnum | J:276797 |
| Mgi Id | MGI:6287090 | Doi | 10.1038/s41467-019-09375-8 |
| Citation | Ye X, et al. (2019) Oncogenic potential of truncated RXRalpha during colitis-associated colorectal tumorigenesis by promoting IL-6-STAT3 signaling. Nat Commun 10(1):1463 |
| abstractText | Retinoid X receptor-alpha (RXRalpha) is a potent regulator of inflammatory responses; however, its therapeutic potential for inflammatory cancer remains to be explored. We previously discovered that RXRalpha is abnormally cleaved in tumor cells and tissues, producing a truncated RXRalpha (tRXRalpha). Here, we show that transgenic expression of tRXRalpha in mice accelerates the development of colitis-associated colon cancer (CAC). The tumorigenic effect of tRXRalpha 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 tRXRalpha and TRAF6 in the cytoplasm of macrophages, leading to TRAF6 ubiquitination and subsequent activation of the NF-kappaB inflammatory pathway. K-80003, a tRXRalpha modulator derived from nonsteroidal anti-inflammatory drug (NSAID) sulindac, suppresses the growth of tRXRalpha-mediated colorectal tumor by inhibiting the NF-kappaB-IL-6-STAT3 signaling cascade. These results provide new insight into tRXRalpha action and identify a promising tRXRalpha ligand for treating CAC. |
