Abstract
Multidrug resistance (MDR) is a major obstacle in the successful treatment of ovarian cancer. One of the most common causes of MDR is overexpression of P-glycoprotein (P-gp), encoded by the MDR1 gene. The MDR1 gene is a direct target of the Wnt/β-catenin signaling pathway, which plays an important role in ovarian cancer. Peroxisome proliferator-activated receptor γ (PPARγ) ligands have been found to protect against development of cancer through the Wnt/β-catenin pathway. To investigate the effect of PPARγ ligands on MDR1/P-gp expression, we treated a MDR ovarian cancer cell subline, A2780/Taxol, with different concentrations of rosiglitazone (Rosi), a member of the synthetic PPARγ ligands. Rosi downregulated FZD1 and MDR1/P-gp expression in a concentration-dependent manner. In addition, nuclear β-catenin levels and its transcriptional activity decreased significantly. In conclusion, Rosi may reverse MDR of ovarian cancer cells by downregulating the Wnt/β-catenin pathway with the suppression of FZD1.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Active Transport, Cell Nucleus
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Anilides / pharmacology
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Cisplatin / pharmacology
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Down-Regulation
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Doxorubicin / pharmacology
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Drug Resistance, Multiple / drug effects
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Drug Resistance, Neoplasm / drug effects*
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Female
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Fluorouracil / pharmacology
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Frizzled Receptors / antagonists & inhibitors
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Frizzled Receptors / metabolism
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Humans
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Ovarian Neoplasms
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PPAR gamma / agonists*
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PPAR gamma / antagonists & inhibitors
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PPAR gamma / metabolism
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Paclitaxel / pharmacology
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Rosiglitazone
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Signal Transduction
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Thiazolidinediones / pharmacology*
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Transcription, Genetic
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Wnt Proteins / metabolism
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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2-chloro-5-nitrobenzanilide
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Anilides
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Antineoplastic Agents
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FZD1 protein, human
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Frizzled Receptors
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PPAR gamma
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Thiazolidinediones
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Wnt Proteins
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beta Catenin
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Rosiglitazone
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Doxorubicin
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Paclitaxel
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Cisplatin
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Fluorouracil