title: HNF4α induced chemosensitivity to oxaliplatin and 5-FU mediated by OCT1 and CNT3 in renal cell carcinoma.
abstract: Increased expression of transporters-mediating uptake of antineoplastic drugs could render renal cell carcinoma (RCC) more sensitive to chemotherapy. Here, we studied the effect of hepatocyte nuclear factor 4α (HNF4α) on the expression of selected uptake transporters in RCC lines. Organic cation transporters (OCTs) and organic anion transporters (OATs) mRNA levels in HNF4α-transfected RCCs were measured by real-time PCR. Expression of HNF4α, β-catenin, N-cadherin, and E-cadherin was detected by immunofluorescence. OCT1, OAT2, and concentrative nucleoside transporter 3 (CNT3) were tested using tritium-labeled substrates and an apoptosis assay. Most RCC did not express uptake transporters in the absence or presence of HNF4α. In RCCNG1 cells, HNF4α-expression increased the chemosensitivity to oxaliplatin and enhanced the accumulation of methyl-4-phenylpyridinium acetate, a model substrate for OCT1. Furthermore, HNF4α enhanced OAT2 mRNA and increased caspase-3 activity upon incubation with a purported OAT2 substrate, 5-fluorouracil (5-FU). However, functional OAT2 protein was not upregulated. CNT3 mRNA was significantly elevated by HNF4α. Inhibition of CNT3-mediated uridine uptake by 5-FU metabolite 5-fluoro-2'-deoxyuridine suggested the involvement of CNT3 in increased caspase-3 activity. Our data suggest that HNF4α increases the expression of OCT1 and CNT3 in RCCNG1 cells, thereby increasing the chemosensitivity of tumor cells to oxaliplatin and 5-FU.
authors.affiliation: Systemic Physiology and Pathophysiology, University Medical Center Goettingen, Goettingen, 37073, Germany; PortaCellTec Biosciences GmbH, Goettingen, 37073, Germany.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Hagos
authors.forename: Waja
authors.initials: W
authors.lastname: Wegner
authors.forename: Annett
authors.initials: A
authors.lastname: Kuehne
authors.forename: Saskia
authors.initials: S
authors.lastname: Floerl
authors.forename: Venkata V V R
authors.initials: VV
authors.lastname: Marada
authors.forename: Gerhard
authors.initials: G
authors.lastname: Burckhardt
authors.forename: Maja
authors.initials: M
authors.lastname: Henjakovic
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D005472:Fluorouracil / Q000494:pharmacology*; D051557:Hepatocyte Nuclear Factor 4 / Q000502:physiology*; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology*; D026901:Membrane Transport Proteins / Q000502:physiology*; D027702:Organic Cation Transporter 1 / Q000502:physiology*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D026901:Membrane Transport Proteins; D027702:Organic Cation Transporter 1; D009944:Organoplatinum Compounds; C065171:cif nucleoside transporter; D000077150:Oxaliplatin; D005472:Fluorouracil
keywords: drug resistance; drug transport; organic anion transporters (OAT); organic cation transporters (OCT); renal transport