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The small-molecule protein ligand interface stabiliser E7820 induces differential cell line specific responses of integrin α2 expression

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Title: The small-molecule protein ligand interface stabiliser E7820 induces differential cell line specific responses of integrin α2 expression
Authors: Hülskamp, Michael David, Kronenberg, Daniel, Stange, Richard
Contributors: Universitäts- und Landesbibliothek Münster
Source: BMC Cancer
BMC Cancer, Vol 21, Iss 1, Pp 1-12 (2021)
Publisher Information: Springer Science and Business Media LLC, 2021.
Publication Year: 2021
Subject Terms: 0301 basic medicine, Indoles, 610 Medicine and health, SPLINTS, Integrin alpha2, Ligands, Cell Line, Mice, 03 medical and health sciences, Human Umbilical Vein Endothelial Cells, Animals, Humans, Protein Isoforms, ddc:610, Promoter Regions, Genetic, CAPERα, RC254-282, Protein Isoforms/antagonists, Cell Line [MeSH], Osteoblasts/metabolism [MeSH], Trans-Activators/genetics [MeSH], Proteolysis/drug effects [MeSH], Ligands [MeSH], Indoles/pharmacology [MeSH], Integrin alpha2/genetics [MeSH], Up-Regulation/drug effects [MeSH], Protein Isoforms/metabolism [MeSH], RNA-Binding Proteins/metabolism [MeSH], Humans [MeSH], Human Umbilical Vein Endothelial Cells/metabolism [MeSH], Sulfonamides/pharmacology [MeSH], Animals [MeSH], Integrin α2, Protein Isoforms/genetics [MeSH], Promoter Regions, Genetic/genetics [MeSH], Mice [MeSH], Human Umbilical Vein Endothelial Cells/drug effects [MeSH], RNA-Binding Proteins/genetics [MeSH], Integrin alpha2/metabolism [MeSH], RNA-Binding Proteins/antagonists, Research, Trans-Activators/antagonists, E7820, Trans-Activators/metabolism [MeSH], Osteoblasts/drug effects [MeSH], Sulfonamides, 0303 health sciences, Osteoblasts, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RNA-Binding Proteins, Up-Regulation, 3. Good health, Medicine and health, Proteolysis, Trans-Activators
Description: Background The mechanism of small-molecule stabilised protein-protein interactions is of growing interest in the pharmacological discovery process. A plethora of different substances including the aromatic sulphonamide E7820 have been identified to act by such a mechanism. The process of E7820 induced CAPERα degradation and the resultant transcriptional down regulation of integrin α2 expression has previously been described for a variety of different cell lines and been made responsible for E7820’s antiangiogenic activity. Currently the application of E7820 in the treatment of various malignancies including pancreas carcinoma and breast cancer is being investigated in pre-clinical and clinical trials. It has been shown, that integrin α2 deficiency has beneficial effects on bone homeostasis in mice. To transfer E7820 treatment to bone-related pathologies, as non-healing fractures, osteoporosis and bone cancer might therefore be beneficial. However, at present no data is available on the effect of E7820 on osseous cells or skeletal malignancies. Methods Pre-osteoblastic (MC3T3 and Saos-2) cells and endothelial (eEnd2 cells and HUVECs) cells, each of human and murine origin respectively, were investigated. Vitality assay with different concentrations of E7820 were performed. All consecutive experiments were done at a final concentration of 50 ng/ml E7820. The expression and production of integrin α2 and CAPERα were investigated by quantitative real-time PCR and western blotting. Expression of CAPERα splice forms was differentiated by semi-quantitiative reverse transcriptase PCR. Results Here we present the first data showing that E7820 can increase integrin α2 expression in the pre-osteoblast MC3T3 cell line whilst also reproducing canonical E7820 activity in HUVECs. We show that the aberrant activity of E7820 in MC3T3 cells is likely due to differential activity of CAPERα at the integrin α2 promoter, rather than due to differential CAPERα degradation or differential expression of CAPERα spliceforms. Conclusion The results presented here indicate that E7820 may not be suitable to treat certain malignancies of musculoskeletal origin, due to the increase in integrin α2 expression it may induce. Further investigation of the differential functioning of CAPERα and the integrin α2 promoter in cells of various origin would however be necessary to more clearly differentiate between cell lines that will positively respond to E7820 from those that will not.
Document Type: Article
Conference object
Other literature type
File Description: application/pdf
Language: English
ISSN: 1471-2407
DOI: 10.1186/s12885-021-08301-w
DOI: 10.17879/70079472508
Access URL: https://bmccancer.biomedcentral.com/track/pdf/10.1186/s12885-021-08301-w
https://pubmed.ncbi.nlm.nih.gov/34006252
https://doaj.org/article/b07632ce4aa24c3e908f7c29ea4bdb3b
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-021-08301-w
https://link.springer.com/article/10.1186/s12885-021-08301-w
https://link.springer.com/content/pdf/10.1186/s12885-021-08301-w.pdf
https://europepmc.org/article/MED/34006252
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132423
https://www.ncbi.nlm.nih.gov/pubmed/34006252
https://repository.publisso.de/resource/frl:6462829
https://repositorium.uni-muenster.de/transfer/miami/c6ff0dff-7a18-478e-9edf-e56ff41c6864
Rights: CC BY
Accession Number: edsair.doi.dedup.....12a2d9287612a4dc333f1feee7470043
Database: OpenAIRE
Description
Abstract:Background The mechanism of small-molecule stabilised protein-protein interactions is of growing interest in the pharmacological discovery process. A plethora of different substances including the aromatic sulphonamide E7820 have been identified to act by such a mechanism. The process of E7820 induced CAPERα degradation and the resultant transcriptional down regulation of integrin α2 expression has previously been described for a variety of different cell lines and been made responsible for E7820’s antiangiogenic activity. Currently the application of E7820 in the treatment of various malignancies including pancreas carcinoma and breast cancer is being investigated in pre-clinical and clinical trials. It has been shown, that integrin α2 deficiency has beneficial effects on bone homeostasis in mice. To transfer E7820 treatment to bone-related pathologies, as non-healing fractures, osteoporosis and bone cancer might therefore be beneficial. However, at present no data is available on the effect of E7820 on osseous cells or skeletal malignancies. Methods Pre-osteoblastic (MC3T3 and Saos-2) cells and endothelial (eEnd2 cells and HUVECs) cells, each of human and murine origin respectively, were investigated. Vitality assay with different concentrations of E7820 were performed. All consecutive experiments were done at a final concentration of 50 ng/ml E7820. The expression and production of integrin α2 and CAPERα were investigated by quantitative real-time PCR and western blotting. Expression of CAPERα splice forms was differentiated by semi-quantitiative reverse transcriptase PCR. Results Here we present the first data showing that E7820 can increase integrin α2 expression in the pre-osteoblast MC3T3 cell line whilst also reproducing canonical E7820 activity in HUVECs. We show that the aberrant activity of E7820 in MC3T3 cells is likely due to differential activity of CAPERα at the integrin α2 promoter, rather than due to differential CAPERα degradation or differential expression of CAPERα spliceforms. Conclusion The results presented here indicate that E7820 may not be suitable to treat certain malignancies of musculoskeletal origin, due to the increase in integrin α2 expression it may induce. Further investigation of the differential functioning of CAPERα and the integrin α2 promoter in cells of various origin would however be necessary to more clearly differentiate between cell lines that will positively respond to E7820 from those that will not.
ISSN:14712407
DOI:10.1186/s12885-021-08301-w