Abstract
Cancer stem cells (CSCs), a subpopulation of tumor cells with the features of self-renewal, tumor initiation, and insensitivity to common physical and chemical agents, are the key to cancer relapses, metastasis, and resistance. Accessible CSCs inhibitory strategies are primarily based on small molecule drugs, yet toxicity limits their application. Here, we report a liposome loaded with low toxicity and high effectiveness of miriplatin, lipo-miriplatin (LMPt) with high miriplatin loading, and robust stability, exhibiting a superior inhibitory effect on CSCs and non-CSCs. LMPt predominantly inhibits the survival of oxaliplatin-resistant (OXA-resistant) cells composed of CSCs. Furthermore, LMPt directly blocks stemness features of self-renewal, tumor initiation, unlimited proliferation, metastasis, and insensitivity. In mechanistic exploration, RNA sequencing (RNA-seq) revealed that LMPt downregulates the levels of pro-stemness proteins and that the β-catenin-mediated stemness pathway is enriched. Further research shows that either in adherent cells or 3D-spheres, the β-catenin-OCT4/NANOG axis, the vital pathway to maintain stemness, is depressed by LMPt. The consecutive activation of the β-catenin pathway induced by mutant β-catenin (S33Y) and OCT4/NANOG overexpression restores LMPt's anti-CSCs effect, elucidating the key role of the β-catenin-OCT4/NANOG axis. Further studies revealed that the strengthened binding of β-catenin and β-TrCP initiates ubiquitination and degradation of β-catenin induced by LMPt. In addition, the ApcMin/+ transgenic mouse model, in which colon tumors are spontaneously formed, demonstrates LMPt's potent anti-non-CSCs activity in vivo.