Oncogenic Role And Molecular Mechanism Of TRXRα In Colon Carcinogenesis

Retinoid X receptor-alpha(RXRa),an unique member of the nuclear receptor(NR)superfamily,plays an important role in many biological processes such as growth,differentiation,metabolism,immunity and death.Abnormal expression and function of RXRa have been found to associate with the development of cancer and diseases.RXRa is an intruging and validated drug target for pharmacologic interventions.Recent studies showed that the N-terminally truncated RXRa(tRXRa)was highly expressed in many types of tumor cells and inflammatory cells,and interacted with p85a,a regulatory subunit of PI3K to activate AKT and promote tumor cell growth.Full-length RXRa can not interact with p85a and promote cell growth.In addition,we found that non-steroidal anti-inflammatory drug(NSAID)sulindac and its derivatives K-80003 can bind to tRXRa,inhibit the interaction of tRXRa and p85a and induce tumor cell apoptosis.Interestingly,the combination of K-80003 and tRXRa promoted the formation of tRXRa tetramers,thereby inhibiting tRXR-mediated inflammatory signaling.Here,we focus on the role of tRXRa in the development of colon cancer,as well as the therapeutic effect of K-80003 on colon cancer.Firstly,we generated transgenic tRXRa-flox mice which can overexpress tRXRa in specific tissue or in many tissues by crossing with different types of Cre mice.Using a colitis-associated cancer model,we found that tRXRa overexpressed in many tissues transgenic mice(Tg-tRXRa mice)have more tumor load and tumor multiplicity than wild type mice,accompanied with enhanced cytokines expression including IL-6 and TNFa,macrophages infiltration and the phosphorylation of STAT3.tRXRa promoted the tumorigenesis of colitis-associated colon cancer due to its expression in myeloid cells but not intestinal epithelial cells through induction of cytokine production and STAT3 activation.Tg-tRXRa mice were more resistant in accute DSS treatment,as a result of early activation of STAT3.Mechanistic studies revealed that tRXRa interacted with TRAF6 in the cytoplasm of macrophages,resulting in TRAF6 ubiquitination and induction of the IKK/NF-κB pathway.Furthermore,we found that the tRXRa inhibitor K-80003,a derivative of NSAID Sulindac,effectively inhibited the growth of tRXRa-mediated colorectal tumor by inhibiting tRXRa interaction with TRAF6 and tRXRa activation of the NF-κB-IL-6-STAT3 signaling cascade.Together,these results provide a new nongenomic mechanism of tRXRa and identify a promising tRXRa modulator for colon cancer therapy.