Targeting cholesterol biosynthesis for AT/RT: comprehensive expression analysis and validation in newly established AT/RT cell line

Atypical teratoid/rhabdoid (AT/RT) is a rare and highly malignant tumor of the central nervous system (CNS). It is most commonly found in children less than 5 years of age and is associated with inactivation of loss of function of SMARCB1/INI1. An experimental model for AT/RT is necessary to develop...

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Bibliographic Details
Published in:Human cell : official journal of Human Cell Research Society 2024-03, Vol.37 (2), p.523-530
Main Authors: Matsumoto, Fumitaka, Yokogami, Kiyotaka, Yamada, Ai, Moritake, Hiroshi, Watanabe, Takashi, Yamashita, Shinji, Sato, Yuichiro, Takeshima, Hideo
Format: Article
Language:English
Subjects:
Apoptosis
Biomedical and Life Sciences
Biosynthesis
Cell Biology
Cell Line
Central nervous system
Child
Cholesterol
Exons
Gene deletion
Gynecology
Humans
Life Sciences
Oncology
Reproductive Medicine
Simvastatin
Stem Cells
Stop codon
Surgery
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Summary:Atypical teratoid/rhabdoid (AT/RT) is a rare and highly malignant tumor of the central nervous system (CNS). It is most commonly found in children less than 5 years of age and is associated with inactivation of loss of function of SMARCB1/INI1. An experimental model for AT/RT is necessary to develop new and effective therapies. We established a patient-derived new cell line (MZ611ATRT), which showed loss of BAF-47. MZ611ATRT genetically features somatic heterozygous deletion of SMARCB1 and single nucleotide deletion of the residual allele, exon 5 ([c.541delC]), resulting in a stop codon at codon 954 by frameshift. We assessed the RNA-sequencing data of the other two AT/RT cell lines with forced expression of SMARCB1 available from public databases. We found SMARCB1 overexpression significantly down-regulates the expression of a group of enzymes related to cholesterol biosynthesis. Simvastatin was highly sensitive against MZ611ATRT cells and induced apoptosis (IC 50 was 3.098 µM for MZ611ATRT, 41.88uM for U-87 MG, 23.34uM for IOMM-Lee, and 18.12uM for U-251 MG.). Pathways involved in cholesterol biosynthesis may be new targets for adjuvant therapy of AT/RT.
ISSN:1749-0774
0914-7470
1749-0774
DOI:10.1007/s13577-023-01022-1