Back to Search
Start Over
Loss of CUL4A expression is underlying cisplatin hypersensitivity in colorectal carcinoma cells with acquired trabectedin resistance.
- 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.
- Subjects :
- Cell Line, Tumor
Colorectal Neoplasms genetics
Cullin Proteins antagonists & inhibitors
DNA Repair drug effects
DNA Repair genetics
Drug Resistance, Neoplasm drug effects
Gene Expression Regulation, Neoplastic drug effects
Gene Knockdown Techniques
Genes, p53
HCT116 Cells
Humans
RNA, Small Interfering pharmacology
Trabectedin
Cisplatin therapeutic use
Colorectal Neoplasms drug therapy
Cullin Proteins genetics
Dioxoles therapeutic use
Drug Resistance, Neoplasm genetics
Tetrahydroisoquinolines therapeutic use
Subjects
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