Gli1 contributes to cellular resistance to cisplatin through altered cellular accumulation of the drug

Amable,Lauren; Fain,Jason; Gavin,Elaine; Reed,Eddie

doi:10.3892/or.2014.3257

Gli1 contributes to cellular resistance to cisplatin through altered cellular accumulation of the drug

Authors:
- Lauren Amable
- Jason Fain
- Elaine Gavin
- Eddie Reed
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Affiliations: National Institute on Minority Health and Health Disparities, National Institutes of Health, Bethesda, MD 20892, USA, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
Published online on: June 12, 2014 https://doi.org/10.3892/or.2014.3257
Pages: 469-474
Copyright: © Amable et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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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.

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