Morusin inhibits the growth of human colorectal cancer HCT116-derived sphere-forming cells via the inactivation of Akt pathway

The existence of colorectal cancer stem-like cells (CSC) is responsible for the failure of current treatments against colorectal cancer. Therefore, novel therapies need be developed to target CSCs. Some natural agents, including morusin have been proposed as possible candidates for this purpose. Morusin has been shown to exert antitumor effects. In the present study, it is demonstrated that morusin exerts antitumor effects on colorectal CSCs (CCSCs). The viability of human CCSCs was enhanced when the CCSCs formed spheroids in a serum-free and non-adhesive floating culture system. HCT116 sphere cells exhibited an increased proliferative capacity and a higher expression of stemness markers [octamer-binding transcription factor 4 (Oct4), Sox2 and Nanog]. Morusin inhibited the development of cancer spheroids and suppressed the growth of sphere cells via the induction of cell cycle arrest. Similarly, morusin decreased the expression levels of the stemness markers, Nanog and Oct4. The data partially revealed the molecular mechanisms involved: β-catenin signaling maintains the growth of CSCs and directly modulates the expression of Nanog and Oct4. Morusin suppressed the activity of β-catenin signaling via the inactivation of Akt; the executive β-catenin/TCF4 complex and the downstream targets, c-Myc, survivin and cyclin D1, were also downregulated. Moreover, the morusin-induced inactivation of Akt also increased the expression of p21Cip1/WAF1 and p27Kip, which can block the cell cycle by interacting with cyclin-dependent kinase (CDK) complexes. On the whole, the present study demonstrates that morusin inhibited the growth of colorectal cancer sphere cells, which were enriched with CCSCs via the inactivation of the Akt pathway.