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

Abstract Background Lipid 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, an...

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Autores principales:	So‐Yeon Park, Jee‐Heun Kim, Jang‐Hyun Choi, Choong‐Jae Lee, Won‐Jae Lee, Sehoon Park, Zee‐Yong Park, Jeong‐Heum Baek, Jeong‐Seok Nam
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	cancer stem‐like cells checkpoint kinase 1 colorectal cancer lipid rafts Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/f47a733a21c74f5f9016ff2fd65e482f
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spelling	oai:doaj.org-article:f47a733a21c74f5f9016ff2fd65e482f2021-11-30T07:25:37ZLipid raft‐disrupting miltefosine preferentially induces the death of colorectal cancer stem‐like cells2001-132610.1002/ctm2.552https://doaj.org/article/f47a733a21c74f5f9016ff2fd65e482f2021-11-01T00:00:00Zhttps://doi.org/10.1002/ctm2.552https://doaj.org/toc/2001-1326Abstract Background Lipid 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. Methods This 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. Results Miltefosine 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. Conclusion Our 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.So‐Yeon ParkJee‐Heun KimJang‐Hyun ChoiChoong‐Jae LeeWon‐Jae LeeSehoon ParkZee‐Yong ParkJeong‐Heum BaekJeong‐Seok NamWileyarticlecancer stem‐like cellscheckpoint kinase 1colorectal cancerlipid raftsMedicine (General)R5-920ENClinical and Translational Medicine, Vol 11, Iss 11, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cancer stem‐like cells checkpoint kinase 1 colorectal cancer lipid rafts Medicine (General) R5-920
spellingShingle	cancer stem‐like cells checkpoint kinase 1 colorectal cancer lipid rafts Medicine (General) R5-920 So‐Yeon Park Jee‐Heun Kim Jang‐Hyun Choi Choong‐Jae Lee Won‐Jae Lee Sehoon Park Zee‐Yong Park Jeong‐Heum Baek Jeong‐Seok Nam Lipid raft‐disrupting miltefosine preferentially induces the death of colorectal cancer stem‐like cells
description	Abstract Background Lipid 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. Methods This 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. Results Miltefosine 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. Conclusion Our 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.
format	article
author	So‐Yeon Park Jee‐Heun Kim Jang‐Hyun Choi Choong‐Jae Lee Won‐Jae Lee Sehoon Park Zee‐Yong Park Jeong‐Heum Baek Jeong‐Seok Nam
author_facet	So‐Yeon Park Jee‐Heun Kim Jang‐Hyun Choi Choong‐Jae Lee Won‐Jae Lee Sehoon Park Zee‐Yong Park Jeong‐Heum Baek Jeong‐Seok Nam
author_sort	So‐Yeon Park
title	Lipid raft‐disrupting miltefosine preferentially induces the death of colorectal cancer stem‐like cells
title_short	Lipid raft‐disrupting miltefosine preferentially induces the death of colorectal cancer stem‐like cells
title_full	Lipid raft‐disrupting miltefosine preferentially induces the death of colorectal cancer stem‐like cells
title_fullStr	Lipid raft‐disrupting miltefosine preferentially induces the death of colorectal cancer stem‐like cells
title_full_unstemmed	Lipid raft‐disrupting miltefosine preferentially induces the death of colorectal cancer stem‐like cells
title_sort	lipid raft‐disrupting miltefosine preferentially induces the death of colorectal cancer stem‐like cells
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/f47a733a21c74f5f9016ff2fd65e482f
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Lipid raft‐disrupting miltefosine preferentially induces the death of colorectal cancer stem‐like cells

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