The Mechanism And Anti-tumor Activity Of New RXRα-based Mitotic Agent XS060 And Its Derivates

Altered expression,modification,function or subcellular localization of retinoid X receptor alpha(RXRα),a unique member of the the nuclear receptor superfamily,are implicated in the development of tumors,making RXRa an attractive target for developing new cancer therapeutics.Aberrations in cell-cycle progression is a hallmark of cancer.However,the existing mitosis targeting drugs could not distinguish the difference between malignant and normal cells,causing significant toxicity.Therefore,more effective and less toxic mitosis inhibitors selectively targeting tumor cells are urgently needed.Spindle assembly checkpoint(SAC)is a major cell-cycle control mechanism in mitosis.As a spindle assembly center,centrosome plays a critical role in mitotic progression.Thus,kinases regulating centrosome dynamics and spindle function hold great promise for developing anticancer therapies.Recently,we found that RXRa is specifically phosphorylated by CDK1 at the onset of mitosis,which promotes its traslocation to the centrosome and interaction with PLK1,resulting in PLK1 activation and centrosome maturation.Moreover,a synthestic compound,XS060,which binds RXRa to selectively inhibit its interaction with PLK1 was identified.XS060 inhibits mitotic progression,leading to apoptosis of tumor cells.However,the mechanism by which XS060 inhibits mitosis and induces apoptosis remains to be fully determined.In addition,the efficacy and selectiveity of XS060 need to be improved.In studying the mechanism by which XS060 inhibits RXRα-mediated mitotic activities,we found that it can inhibit the co-localization of RXRa and PLK1 at the centrosome,PLK1 phosphorylation and activation,and centrosome maturation,resulting in abnormal spindle assembly and chromosomal arrangement disorder,mitotic arrest and subsequently apoptosis.p-RXRa is highly expressed in hepatocellular carcinoma,contributing to the occurrence and development of liver cancer.In this study,we found that XS060 can effectively induce mitotic arrest and apoptosis in hepatoma cell lines including SK-Hepl and BEL-7402.Moreover,XS060 effectively inhibited the growth of HCC xenograft tumor in mice without apparent toxic and side effects.We also identified an improved XS060 analog,B10,which is more effective than XS060 on binding RXRα,inhibiting RXRα-mediated centrosomal activities,and inducing mitotic arrest and apoptosis of cancer cells.Our results provide mechanistic insight into the role of RXRa and XS060 in regulating mitotic progression and identify an improved RXRa ligand that warrants further evaluation and stud...