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

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.

• Authors: Xiaohong Ye, Hua Wu, Luoyan Sheng, Yi-Xin Liu, Fang Ye, Mo Wang, Hu Zhou, Ying Su, Xiao-Kun Zhang
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 1463 (04 01 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 30931933 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Culture Media, Conditioned
• Interleukin-6
• NF-kappa B
• Retinoid X Receptor alpha
• STAT3 Transcription Factor
• Stat3 protein, mouse
• TNF Receptor-Associated Factor 6
• interleukin-6, mouse
• Sulindac
• K-80003

Topics

• Animals
• Carcinogenesis (genetics, immunology)
• Colitis (genetics, immunology)
• Colitis, Ulcerative (immunology)
• Colon (drug effects, immunology, metabolism)
• Colorectal Neoplasms (genetics, immunology)
• Culture Media, Conditioned
• Disease Models, Animal
• HCT116 Cells
• Humans
• Inflammation
• Interleukin-6 (immunology)
• Macrophages (immunology)
• Mice
• NF-kappa B (immunology)
• Retinoid X Receptor alpha (genetics, immunology)
• STAT3 Transcription Factor (immunology)
• Signal Transduction
• Sulindac (analogs & derivatives, pharmacology)
• TNF Receptor-Associated Factor 6 (immunology)