Disruption of Lipid Raft Microdomains, Regulation of CD38, TP53, and MYC Signaling, and Induction of Apoptosis by Lomitapide in Multiple Myeloma Cells

Publication type:
Journal article
Metadata:
Autoren
  • Mohamed EM Saeed
  • Joelle C Boulos
  • Sabrina B Muecklich
  • Ellen Leich
  • Manik Chatterjee
  • Sabine M Klauck
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000874838700001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.21873/cgp.20339
eISSN
1790-6245
Externe Identifier
  • Clarivate Analytics Document Solution ID: 5R9QU
  • PubMed Identifier: 35985681
ISSN
1109-6535
Ausgabe der Veröffentlichung
5
Zeitschrift
CANCER GENOMICS & PROTEOMICS
Schlüsselwörter
  • e-mail
  • efferth@uni-mainz.de Key Words
  • Cholesterol
  • drug repurposing
  • lipid rafts
  • microarray analyses
Paginierung
540 - 555
Datum der Veröffentlichung
2022
Status
Published
Titel
Disruption of Lipid Raft Microdomains, Regulation of CD38, TP53, and MYC Signaling, and Induction of Apoptosis by Lomitapide in Multiple Myeloma Cells
Sub types
  • Article
Ausgabe der Zeitschrift
19

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • MOHAMED EM SAEED
  • JOELLE C BOULOS
  • SABRINA B MÜCKLICH
  • ELLEN LEICH
  • MANIK CHATTERJEE
  • SABINE M KLAUCK
  • THOMAS EFFERTH
DOI
10.21873/cgp.20339
eISSN
1790-6245
ISSN
1109-6535
Ausgabe der Veröffentlichung
5
Zeitschrift
Cancer Genomics - Proteomics
Sprache
en
Online publication date
2022
Paginierung
540 - 555
Datum der Veröffentlichung
2022
Status
Published
Herausgeber
Anticancer Research USA Inc.
Herausgeber URL
http://dx.doi.org/10.21873/cgp.20339
Datum der Datenerfassung
2022
Titel
Disruption of Lipid Raft Microdomains, Regulation of CD38, TP53, and MYC Signaling, and Induction of Apoptosis by Lomitapide in Multiple Myeloma Cells
Ausgabe der Zeitschrift
19

Data source: Crossref

Abstract
<h4>Background/aim</h4>Multiple myeloma (MM) is characterized by accumulation of a malignant clone of plasma cells in the bone marrow. Curative treatments are not yet available. Therefore, we undertook a drug repurposing approach to identify possible candidates from a chemical library of 1,230 FDA-approved drugs by virtual drug screening. As a target, we have chosen the non-receptor Bruton's tyrosine kinase (BTK) which is one of the main regulators of the MM biomarker CD38.<h4>Materials and methods</h4>In silico virtual screening was performed by using PyRx. Flow cytometry was applied for cell cycle and apoptosis analysis. Furthermore, protein and gene expression was determined by western blotting and microarray hybridization. Lipid raft staining was observed by confocal microscopy.<h4>Results</h4>The in silico identified lipid-lowering lomitapide presented with the strongest cytotoxicity among the top 10 drug candidates. This drug arrested the cell cycle in the G<sub>2</sub>/M phase and induced apoptosis in MM cells. Western blot analyses revealed that treatment with lomitapide induced cleavage of the apoptosis regulator PARP and reduced the expression of CD38, an integral part of lipid rafts. Using confocal microscopy, we further observed that lipid raft microdomain formation in MM cells was inhibited by lomitapide. In four MM cell lines (KMS-12-BM, NCI-H929, RPMI-8226, and MOLP-8) treated with lomitapide, microarray analyses showed not only that the expression of CD38 and BTK was down-regulated, but also that the tumor suppressor gene TP53 and the oncogene c-MYC were among the top deregulated genes. Further analysis of these data by Ingenuity pathway analysis (IPA) suggested that lomitapide interferes with the cross-talk of CD38 and BTK and apoptosis-regulating genes via TP53 and c-MYC.<h4>Conclusion</h4>Lomitapide treatment led to disruption of lipid raft domains and induction of pro-apoptotic factors and might, therefore, be considered as a potential therapeutic agent in MM.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
Autoren
  • Mohamed EM Saeed
  • Joelle C Boulos
  • Sabrina B Mücklich
  • Ellen Leich
  • Manik Chatterjee
  • Sabine M Klauck
  • Thomas Efferth
DOI
10.21873/cgp.20339
eISSN
1790-6245
Externe Identifier
  • PubMed Identifier: 35985681
  • PubMed Central ID: PMC9353726
Open access
false
ISSN
1109-6535
Ausgabe der Veröffentlichung
5
Zeitschrift
Cancer genomics & proteomics
Schlüsselwörter
  • Cell Line, Tumor
  • Membrane Microdomains
  • Humans
  • Multiple Myeloma
  • Benzimidazoles
  • Proto-Oncogene Proteins c-myc
  • Signal Transduction
  • Apoptosis
  • Tumor Suppressor Protein p53
  • ADP-ribosyl Cyclase 1
Sprache
eng
Medium
Print
Paginierung
540 - 555
Datum der Veröffentlichung
2022
Status
Published
Datum der Datenerfassung
2022
Titel
Disruption of Lipid Raft Microdomains, Regulation of CD38, TP53, and MYC Signaling, and Induction of Apoptosis by Lomitapide in Multiple Myeloma Cells.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
19

Files

https://cgp.iiarjournals.org/content/cgp/19/5/540.full.pdf https://europepmc.org/articles/PMC9353726?pdf=render

Data source: Europe PubMed Central

Abstract
BACKGROUND/AIM: Multiple myeloma (MM) is characterized by accumulation of a malignant clone of plasma cells in the bone marrow. Curative treatments are not yet available. Therefore, we undertook a drug repurposing approach to identify possible candidates from a chemical library of 1,230 FDA-approved drugs by virtual drug screening. As a target, we have chosen the non-receptor Bruton's tyrosine kinase (BTK) which is one of the main regulators of the MM biomarker CD38. MATERIALS AND METHODS: In silico virtual screening was performed by using PyRx. Flow cytometry was applied for cell cycle and apoptosis analysis. Furthermore, protein and gene expression was determined by western blotting and microarray hybridization. Lipid raft staining was observed by confocal microscopy. RESULTS: The in silico identified lipid-lowering lomitapide presented with the strongest cytotoxicity among the top 10 drug candidates. This drug arrested the cell cycle in the G2/M phase and induced apoptosis in MM cells. Western blot analyses revealed that treatment with lomitapide induced cleavage of the apoptosis regulator PARP and reduced the expression of CD38, an integral part of lipid rafts. Using confocal microscopy, we further observed that lipid raft microdomain formation in MM cells was inhibited by lomitapide. In four MM cell lines (KMS-12-BM, NCI-H929, RPMI-8226, and MOLP-8) treated with lomitapide, microarray analyses showed not only that the expression of CD38 and BTK was down-regulated, but also that the tumor suppressor gene TP53 and the oncogene c-MYC were among the top deregulated genes. Further analysis of these data by Ingenuity pathway analysis (IPA) suggested that lomitapide interferes with the cross-talk of CD38 and BTK and apoptosis-regulating genes via TP53 and c-MYC. CONCLUSION: Lomitapide treatment led to disruption of lipid raft domains and induction of pro-apoptotic factors and might, therefore, be considered as a potential therapeutic agent in MM.
Date of acceptance
2022
Autoren
  • Mohamed EM Saeed
  • Joelle C Boulos
  • Sabrina B Mücklich
  • Ellen Leich
  • Manik Chatterjee
  • Sabine M Klauck
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/35985681
DOI
10.21873/cgp.20339
eISSN
1790-6245
Externe Identifier
  • PubMed Central ID: PMC9353726
Ausgabe der Veröffentlichung
5
Zeitschrift
Cancer Genomics Proteomics
Schlüsselwörter
  • Cholesterol
  • drug repurposing
  • lipid rafts
  • microarray analyses
  • ADP-ribosyl Cyclase 1
  • Apoptosis
  • Benzimidazoles
  • Cell Line, Tumor
  • Humans
  • Membrane Microdomains
  • Multiple Myeloma
  • Proto-Oncogene Proteins c-myc
  • Signal Transduction
  • Tumor Suppressor Protein p53
Sprache
eng
Country
Greece
Paginierung
540 - 555
PII
19/5/540
Datum der Veröffentlichung
2022
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2022
Titel
Disruption of Lipid Raft Microdomains, Regulation of CD38, TP53, and MYC Signaling, and Induction of Apoptosis by Lomitapide in Multiple Myeloma Cells.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
19

Data source: PubMed

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