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

Xiaohong Ye, Hua Wu, Luoyan Sheng, Yi-xin Liu, Fang Ye, Mo Wang, Hu Zhou, Ying Su and Xiao-kun Zhang ()
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Xiaohong Ye: Xiamen University
Hua Wu: Xiamen University
Luoyan Sheng: Xiamen University
Yi-xin Liu: Xiamen University
Fang Ye: Xiamen University
Mo Wang: Xiamen University
Hu Zhou: Xiamen University
Ying Su: Sanford Burnham Prebys Medical Discovery Institute
Xiao-kun Zhang: Xiamen University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09375-8

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