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Loss of CUL4A expression is underlying cisplatin hypersensitivity in colorectal carcinoma cells with acquired trabectedin resistance.

Authors :
Englinger B
Mair M
Miklos W
Pirker C
Mohr T
van Schoonhoven S
Lötsch D
Körner W
Ferk F
Knasmüller S
Heffeter P
Keppler BK
Grusch M
Berger W
Source :
British journal of cancer [Br J Cancer] 2017 Feb 14; Vol. 116 (4), pp. 489-500. Date of Electronic Publication: 2017 Jan 17.
Publication Year :
2017

Abstract

Background: Colorectal carcinoma (CRC) is the third most common cancer worldwide. Platinum-based anticancer compounds still constitute one mainstay of systemic CRC treatment despite limitations due to adverse effects and resistance development. Trabectedin has shown promising antitumor effects in CRC, however, again resistance development may occur. In this study, we aimed to develop strategies to circumvent or even exploit acquired trabectedin resistance in novel CRC treatment regimens.<br />Methods: Human HCT116 CRC cells were selected for acquired trabectedin resistance in vitro and characterised by cell biological as well as bioinformatic approaches. In vivo xenograft experiments were conducted.<br />Results: Selection of HCT116 cells for trabectedin resistance resulted in p53-independent hypersensitivity of the selected subline against cisplatin. Bioinformatic analyses of mRNA microarray data suggested deregulation of nucleotide excision repair and particularly loss of the ubiquitin ligase CUL4A in trabectedin-selected cells. Indeed, transient knockdown of CUL4A sensitised parental HCT116 cells towards cisplatin. Trabectedin selected but not parental HCT116 xenografts were significantly responsive towards cisplatin treatment.<br />Conclusions: Trabectedin selection-mediated CUL4A loss generates an Achilles heel in CRC cancer cells enabling effective cisplatin treatment. Hence, inclusion of trabectedin in cisplatin-containing cancer treatment regimens might cause profound synergism based on reciprocal resistance prevention.

Details

Language :
English
ISSN :
1532-1827
Volume :
116
Issue :
4
Database :
MEDLINE
Journal :
British journal of cancer
Publication Type :
Academic Journal
Accession number :
28095394
Full Text :
https://doi.org/10.1038/bjc.2016.449