1. Gli1 contributes to cellular resistance to cisplatin through altered cellular accumulation of the drug.
- Author
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Amable L, Fain J, Gavin E, and Reed E
- Subjects
- Binding Sites, Cation Transport Proteins metabolism, Cell Line, Tumor, Copper Transporter 1, DNA Damage, Female, Humans, Organic Cation Transport Proteins metabolism, Zinc Finger Protein GLI1, Antineoplastic Agents pharmacokinetics, Cisplatin pharmacokinetics, Drug Resistance, Neoplasm, Ovarian Neoplasms metabolism, Transcription Factors antagonists & inhibitors, Transcription Factors metabolism
- Abstract
Cellular resistance to platinum anticancer compounds is governed by no less than two molecular processes; DNA repair and cellular accumulation of drug. Gli1 is an upstream regulator of nucleotide excision repair, effecting this process through c-jun. We, therefore, investigated whether Gli1 plays a role in cellular accumulation of cisplatin. Using a Gli1-specific shRNA, we explored the role of Gli1 in the cellular accumulation and efflux of cisplatin, in cisplatin-resistant A2780-CP70 human ovarian cancer cells. When Gli1 is inhibited, cellular uptake of cisplatin was approximately 33% of the level of uptake under control conditions. When Gli1 is inhibited, cellular efflux of cisplatin was completely abrogated, over a 12-h period of observation. We assayed nuclear lysates from these cells, for the ability to bind the DNA sequence that is the Gli-binding site (GBS) in the 5'UTR for each of five known cisplatin transmembrane transporters. Four of these transporters are active in cisplatin uptake; and, one is active in cisplatin efflux. In each case, nuclear lysate from A2780-CP70 cells binds the GBS of the respective cisplatin transport gene. We conclude that Gli1 plays a strong role in total cellular accumulation of cisplatin in these cells; and, that the combined effects on cellular accumulation of drug and on DNA repair may indicate a role for Gli1 in protecting cellular DNA from lethal types of DNA damage.
- Published
- 2014
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