Natural and semisynthetic bile acids as Leukemia Inhibitory Factor (LIF) receptor antagonists

Leukaemia Inhibitory Factor (LIF) is a pleiotropic member of interleukine (IL)-6 cytokine family,1 that regulates cell differentiation, proliferation and survival in embryo and adult cells and is involved in cancer growth and progression. LIF signalling is mediated via the heterodimeric LIF receptor (LIFR) complex, which is formed by LIFR and the glycoprotein (gp) 130. LIFR complex activates the downstream signalling pathways, which include JAK1/STAT3 axis; this signalling is over-regulated in several type of solid tumours, including PDAC, gastric cancer (GC) and hepatocellular carcinoma (HCC).2 Several studies support the suppression of LIFR signalling as putative target to inhibit cell growth and tumour progression in several type of cancers.3 Recently, has been demonstrated that mifepristone-mediate LIFR antagonism inhibits oncogenic signalling and might ameliorate chemoresistance.4 Building on this background and based on steroidal structures of BAs, we performed a similarity screening of natural and semisynthetic bile acid using as query the structure of the LIFR antagonist, such as mifepristone and EC359. Bile Acids (BAs) are steroid derivatives of cholesterol, synthesized in the liver and metabolized by microbiota in the intestine and reabsorbed through the enterohepatic circulation. BAs, especially secondary bile acids, have been reported to have a critical role in gastrointestinal carcinogenesis and breast cancers. However more increasing evidence described their anti-tumour effects. In the present study, we shown that natural bile acid and their metabolites, especially the oxidized forms, are potential LIFR antagonists. Herein we demonstrated that among the various mechanisms of action of BAs as tumour suppressors, their role as onco-suppressors could be mediated by the antagonism on LIFR.