Network pharmacology of triptolide in cancer cells : implications for transcription factor binding
Seo, Ean Jeong ; Dawood, Mona ; Hult, Annika K. LU ; Olsson, Martin L. LU
and Efferth, Thomas
(2021)
In Investigational New Drugs
39(6).
p.1523-1537
- Abstract
Background Triptolide is an active natural product, which inhibits cell proliferation, induces cell apoptosis, suppresses tumor metastasis and improves the effect of other therapeutic treatments in several cancer cell lines by affecting multiple molecules and signaling pathways, such as caspases, heat-shock proteins, DNA damage and NF-ĸB. Purpose We investigated the effect of triptolide towards NF-ĸB and GATA1. Methods We used cell viability assay, compare and cluster analyses of microarray-based mRNA transcriptome-wide expression data, gene promoter binding motif analysis, molecular docking, Ingenuity pathway analysis, NF-ĸB reporter cell assay, and electrophoretic mobility shift assay (EMSA) of GATA1. Results Triptolide inhibited the... (More)
Background Triptolide is an active natural product, which inhibits cell proliferation, induces cell apoptosis, suppresses tumor metastasis and improves the effect of other therapeutic treatments in several cancer cell lines by affecting multiple molecules and signaling pathways, such as caspases, heat-shock proteins, DNA damage and NF-ĸB. Purpose We investigated the effect of triptolide towards NF-ĸB and GATA1. Methods We used cell viability assay, compare and cluster analyses of microarray-based mRNA transcriptome-wide expression data, gene promoter binding motif analysis, molecular docking, Ingenuity pathway analysis, NF-ĸB reporter cell assay, and electrophoretic mobility shift assay (EMSA) of GATA1. Results Triptolide inhibited the growth of drug-sensitive (CCRF-CEM, U87.MG) and drug-resistant cell lines (CEM/ADR5000, U87.MGΔEGFR). Hierarchical cluster analysis showed six major clusters in dendrogram. The sensitive and resistant cell lines were statistically significant (p = 0.65 × 10–2) distributed. The binding motifs of NF-κB (Rel) and of GATA1 proteins were significantly enriched in regions of 25 kb upstream promoter of all genes. IPA showed the networks, biological functions, and canonical pathways influencing the activity of triptolide towards tumor cells. Interestingly, upstream analysis for the 40 genes identified by compare analysis revealed ZFPM1 (friend of GATA protein 1) as top transcription regulator. However, we did not observe any effect of triptolide to the binding of GATA1 in vitro. We confirmed that triptolide inhibited NF-κB activity, and it strongly bound to the pharmacophores of IκB kinase β and NF-κB in silico. Conclusion Triptolide showed promising inhibitory effect toward NF-κB, making it a potential candidate for targeting NF-κB.
(Less)
- author
- Seo, Ean Jeong
; Dawood, Mona
; Hult, Annika K.
LU
; Olsson, Martin L.
LU
and Efferth, Thomas
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Microarrays, Natural products, Network pharmacology, Phytochemicals, Precision medicine
- in
- Investigational New Drugs
- volume
- 39
- issue
- 6
- pages
- 1523 - 1537
- publisher
- Springer
- external identifiers
-
- pmid:34213719
- scopus:85109296285
- ISSN
- 0167-6997
- DOI
- 10.1007/s10637-021-01137-y
- language
- English
- LU publication?
- yes
- id
- 927259d1-af66-49e9-a0f1-a195f7476d98
- date added to LUP
- 2021-08-12 14:31:11
- date last changed
- 2024-06-15 14:07:51
@article{927259d1-af66-49e9-a0f1-a195f7476d98,
abstract = {{<p>Background Triptolide is an active natural product, which inhibits cell proliferation, induces cell apoptosis, suppresses tumor metastasis and improves the effect of other therapeutic treatments in several cancer cell lines by affecting multiple molecules and signaling pathways, such as caspases, heat-shock proteins, DNA damage and NF-ĸB. Purpose We investigated the effect of triptolide towards NF-ĸB and GATA1. Methods We used cell viability assay, compare and cluster analyses of microarray-based mRNA transcriptome-wide expression data, gene promoter binding motif analysis, molecular docking, Ingenuity pathway analysis, NF-ĸB reporter cell assay, and electrophoretic mobility shift assay (EMSA) of GATA1. Results Triptolide inhibited the growth of drug-sensitive (CCRF-CEM, U87.MG) and drug-resistant cell lines (CEM/ADR5000, U87.MGΔEGFR). Hierarchical cluster analysis showed six major clusters in dendrogram. The sensitive and resistant cell lines were statistically significant (p = 0.65 × 10<sup>–2</sup>) distributed. The binding motifs of NF-κB (Rel) and of GATA1 proteins were significantly enriched in regions of 25 kb upstream promoter of all genes. IPA showed the networks, biological functions, and canonical pathways influencing the activity of triptolide towards tumor cells. Interestingly, upstream analysis for the 40 genes identified by compare analysis revealed ZFPM1 (friend of GATA protein 1) as top transcription regulator. However, we did not observe any effect of triptolide to the binding of GATA1 in vitro. We confirmed that triptolide inhibited NF-κB activity, and it strongly bound to the pharmacophores of IκB kinase β and NF-κB in silico. Conclusion Triptolide showed promising inhibitory effect toward NF-κB, making it a potential candidate for targeting NF-κB.</p>}},
author = {{Seo, Ean Jeong and Dawood, Mona and Hult, Annika K. and Olsson, Martin L. and Efferth, Thomas}},
issn = {{0167-6997}},
keywords = {{Microarrays; Natural products; Network pharmacology; Phytochemicals; Precision medicine}},
language = {{eng}},
number = {{6}},
pages = {{1523--1537}},
publisher = {{Springer}},
series = {{Investigational New Drugs}},
title = {{Network pharmacology of triptolide in cancer cells : implications for transcription factor binding}},
url = {{http://dx.doi.org/10.1007/s10637-021-01137-y}},
doi = {{10.1007/s10637-021-01137-y}},
volume = {{39}},
year = {{2021}},
}