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Camptothecin and its analog SN-38, the active metabolite of irinotecan, inhibit binding of the transcriptional regulator and oncoprotein FUBP1 to its DNA target sequence FUSE.

Authors :
Khageh Hosseini, Sabrina
Kolterer, Stefanie
Steiner, Marlene
von Manstein, Viktoria
Gerlach, Katharina
Trojan, Jörg
Waidmann, Oliver
Zeuzem, Stefan
Schulze, Jörg O.
Hahn, Steffen
Steinhilber, Dieter
Gatterdam, Volker
Tampé, Robert
Biondi, Ricardo M.
Proschak, Ewgenij
Zörnig, Martin
Source :
Biochemical Pharmacology. Dec2017, Vol. 146, p53-62. 10p.
Publication Year :
2017

Abstract

The transcriptional regulator FUSE Binding Protein 1 (FUBP1) is overexpressed in more than 80% of all human hepatocellular carcinomas (HCCs) and other solid tumor entities including prostate and colorectal carcinoma. FUBP1 expression is required for HCC tumor cell expansion, and it functions as an important pro-proliferative and anti-apoptotic oncoprotein that binds to the single-stranded DNA sequence FUSE to regulate the transcription of a variety of target genes. In this study, we screened an FDA-approved drug library and discovered that the Topoisomerase I (TOP1) inhibitor camptothecin (CPT) and its derivative 7-ethyl-10-hydroxycamptothecin (SN-38), the active irinotecan metabolite that is used in the clinics in combination with other chemotherapeutics to treat carcinoma, inhibit FUBP1 activity. Both molecules prevent in vitro the binding of FUBP1 to its single-stranded target DNA FUSE , and they induce deregulation of FUBP1 target genes in HCC cells. Our results suggest the interference with the FUBP1/ FUSE interaction as a further molecular mechanism that, in addition to the inactivation of TOP1, may contribute to the therapeutic potential of CPT/SN-38. Targeting of FUBP1 in HCC therapy with SN-38/irinotecan could be a particularly interesting option because of the high FUBP1 levels in HCC cells and their dependency on FUBP1 expression. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00062952
Volume :
146
Database :
Academic Search Index
Journal :
Biochemical Pharmacology
Publication Type :
Academic Journal
Accession number :
126350566
Full Text :
https://doi.org/10.1016/j.bcp.2017.10.003