Lipid raft‐disrupting miltefosine preferentially induces the death of colorectal cancer stem‐like cells

Abstract

BackgroundLipid rafts (LRs), cholesterol‐enriched microdomains on cell membranes, are increasingly viewed as signalling platforms governing critical facets of cancer progression. The phenotype of cancer stem‐like cells (CSCs) presents significant hurdles for successful cancer treatment, and the expression of several CSC markers is associated with LR integrity. However, LR implications in CSCs remain unclear.MethodsThis study evaluated the biological and molecular functions of LRs in colorectal cancer (CRC) by using an LR‐disrupting alkylphospholipid (APL) drug, miltefosine. The mechanistic role of miltefosine in CSC inhibition was examined through normal or tumour intestinal mouse organoid, human CRC cell, CRC xenograft and miltefosine treatment gene expression profile analyses.ResultsMiltefosine suppresses CSC populations and their self‐renewal activities in CRC cells, a CSC‐targeting effect leading to irreversible disruption of tumour‐initiating potential in vivo. Mechanistically, miltefosine reduced the expression of a set of genes, leading to stem cell death. Among them, miltefosine transcriptionally inhibited checkpoint kinase 1 (CHEK1), indicating that LR integrity is essential for CHEK1 expression regulation. In isolated CD44high CSCs, we found that CSCs exhibited stronger therapy resistance than non‐CSC counterparts by preventing cell death through CHEK1‐mediated cell cycle checkpoints. However, inhibition of the LR/CHEK1 axis by miltefosine released cell cycle checkpoints, forcing CSCs to enter inappropriate mitosis with accumulated DNA damage and resulting in catastrophic cell death.ConclusionOur findings underscore the therapeutic potential of LR‐targeting APLs for CRC treatment that overcomes the therapy‐resistant phenotype of CSCs, highlighting the importance of the LR/CHEK1 axis as a novel mechanism of APLs.

Patient-derived rectal cancer organoids—applications in basic and translational cancer research

“…Five studies associated with patient-derived RC organoid application were finally considered. All publications or clinical studies that met the criteria were included in Table 2, and some of the publications and clinical studies excluded are shown in Table 1 (28)(29)(30)(31)(32)(33)(34)(35)(36)(37). They are presented subsequently in this order, reflecting the scientific continuum, moving from the characterization and acquisition of knowledge to the interpretation and finally toward clinical implementation.…”

Miltefosine attenuates inflammation, reduces atherosclerosis, and alters gut microbiota in hyperlipidemic mice

“…Priming of the inflammasome pathway by LPS is dependent on TLR receptors, which are enriched in membrane lipid rafts. Miltefosine-mediated disruption of lipid rafts can attenuate TLR signaling pathway 10,50 , thus we tested the effects of Miltefosine on direct NLRP3 inflammasome activity in live animals. We chose the peritoneal cavity as the site for NLRP3 inflammasome activity as it contains the liver, spleen, GI tract, and a variety of immune cells.…”

The lipid rafts in cancer stem cell: a target to eradicate cancer

“…Cancer cells are previously confirmed to have higher levels of lipid rafts than normal cells [ 11 , 12 ], while emerging evidence indicates that CSCs contain more lipid rafts than cancer cells. That is, the relative amount of lipid rafts: CSCs > cancer cells > normal cells [ 13 ]. Specifically, a study using filipin and conjugated cholera toxin B (CtxB) for plasma membrane cholesterol and GM1 staining showed that the cancer cell lines (PC-3, LNCaP, MCF-7, and MDA-MB-231) have stronger staining than the normal cell lines (PZ-HPV7 and MCF-10A), suggesting higher levels of rafts/ caveolae in the cancer cell lines.…”

“…Regarding the lipid rafts of CSCs, the data from CtxB immunostaining and flow cytometry assay have shown that the levels of lipid rafts in CD44 high colorectal cancer cells are higher, as the median fluorescence intensity ratio of lipid rafts within CD44 high cells is 10%-30% stronger than CD44 low cells. Importantly, CtxB high cells showed a greater sphere‐forming capacity [ 13 ]. In addition, CD133 + pancreatic cancer cells have more caveolin-1and cholesterol than CD133 − cells by Western blotting, real-time PCR and Amplex red cholesterol assay, indicating higher levels of lipid rafts in CD133 + CSCs [ 14 ].…”

“…In parallel, immunofluorescence assays and flow cytometry analysis visually confirmed miltefosine reduces lipid raft levels with a disruption of sphere formation. Similar to in vitro assay, immunostaining assays of xenografted tumors have revealed a decrease in CD44 high cells along with an increase in apoptotic cells after miltefosine treatment [ 13 ]. Meanwhile, several CSC biomarkers have been found in lipid rafts, which are affected by lipid rafts [ 16 – 19 ].…”