Disrupting Lipid Raft by Miltefosine Inhibits Colorectal Cancer Stemness

Abstract

Miltefosine, a recent FDA-approced anti-leishmaniasis drug, was initially developed as a potential anticancer drug and its selective accumulation to a lipid raft on cancer cells seems to related to its anticancer effect, yet its mechanism has not defined. Lipid raft is a highly ordered cholesterol-rich membrane domain which serves as a platform for signaling transduction. Here, we firstly found that lipid raft is significantly enriched in colorectal cancer stem cells(CSCs) than normal colon epithelial cells and cancer cells. Thus, Miltefosine exert significant anti-cancer effect against cancer cells, suggesting its selective anti-cancer effects. In vitro Miltefosine treatment reduced self-renewal and repopulation of CSCs by disrupting lipid raft. Interruption of this scaffolding structure reduces the transcription of Checkpoint Kinase 1 (CHK1), hence, CHK1 inhibitor treatment and gene silencing disrupts CSC capacity of managing DNA damage and induces CSCs to enter mitotic catastrophe. Therefore, purging of CSCs by targeting CHK1 to stimulate mitotic catastrophe may provide the fundamental evidence for oncological application of miltefosine especially in colorectal cancer.