Modulation of drug resistance by artificial transcription factors
| Autor: | Daniel Guthy, Pilar Blancafort, Sharon Bergquist, Bruce E. Torbett, Arndt Brachat, Dennis A Sheeter, Dirk Erdmann, Mario P. Tschan, Carlos F. Barbas |
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| Rok vydání: | 2008 |
| Předmět: |
Zinc finger
Cancer Research Base Sequence Reverse Transcriptase Polymerase Chain Reaction Kinase Drug resistance Biology Pharmacology Oncology Drug Resistance Neoplasm Cell culture Cancer cell Cancer research medicine Humans Transcription factor Gene Etoposide DNA Primers HeLa Cells Transcription Factors medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 7:688-697 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-07-0381 |
| Popis: | The efficiency of chemotherapeutic treatments in cancer patients is often impaired by the acquisition of drug resistance. Cancer cells develop drug resistance through dysregulation of one or more genes or cellular pathways. To isolate efficient regulators of drug resistance in tumor cells, we have adopted a genome-wide scanning approach based on the screening of large libraries of artificial transcription factors (ATFs) made of three and six randomly assembled zinc finger domains. Zinc finger libraries were linked to a VP64 activation domain and delivered into a paclitaxel-sensitive tumor cell line. Following drug treatment, several ATFs were isolated that promoted drug resistance. One of these ATFs, 3ZF-1-VP, promoted paclitaxel resistance in cell lines having mutated or inactivated p53, such as MDA-MB-435 and Kaposi's sarcoma cell lines. 3ZF-1-VP also induced strong resistance to etoposide, vincristine, and cisplatinum. Linkage of a repression domain to the selected ATF resulted in enhanced sensitivity to multiple drugs, particularly vincristine, cisplatinum, and 5-fluorouracil. Small interfering RNA–mediated inhibition of p53 revealed that 3ZF-1-VP activated both p53-dependent and p53-independent mechanisms to promote survival, whereas other ATF required intact p53. Real-time expression analysis and DNA microarrays showed that several ATFs up-regulated targets of p53, such as the cyclin-dependent kinase inhibitor p21WAF1/CIP1, and genes participating in the p14ARF-MDM2-p53 tumor suppressor pathway, such as hDMP1. Thus, ATF can be used to map genes and pathways involved in drug resistance phenotypes and have potential as novel therapeutic agents to inhibit drug resistance. [Mol Cancer Ther 2008;7(3):688–97] |
| Databáze: | OpenAIRE |
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