title: Gli1 contributes to cellular resistance to cisplatin through altered cellular accumulation of the drug.
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.
authors.affiliation: National Institute on Minority Health and Health Disparities, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Amable
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Fain
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Gavin
authors.affiliation: National Institute on Minority Health and Health Disparities, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Eddie
authors.initials: E
authors.lastname: Reed
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001665:Binding Sites; D027682:Cation Transport Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000493:pharmacokinetics*; D000079923:Copper Transporter 1; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C400551:GLI1 protein, human; D027701:Organic Cation Transport Proteins; C490079:SLC31A1 protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D002945:Cisplatin