HNF4[alpha] Induced Chemosensitivity to Oxaliplatin and 5-FU Mediated by OCT1 and CNT3 in Renal Cell Carcinoma

• Published in: Journal of pharmaceutical sciences 2014-10, Vol.103 (10), p.3326
• Main Authors: Hagos, Yohannes, Wegner, Waja, Kuehne, Annett, Floerl, Saskia, Marada, Venkata V V R, Burckhardt, Gerhard, Henjakovic, Maja
• Format: Article
• Language: English
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.24128

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 4[alpha] (HNF4[alpha]) on the expression of selected uptake transporters in RCC lines. Organic cation transporters (OCTs) and organic anion transporters (OATs) mRNA levels in HNF4[alpha]-transfected RCCs were measured by real-time PCR. Expression of HNF4[alpha], [beta]-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 HNF4[alpha]. In RCCNG1 cells, HNF4[alpha]-expression increased the chemosensitivity to oxaliplatin and enhanced the accumulation of methyl-4-phenylpyridinium acetate, a model substrate for OCT1. Furthermore, HNF4[alpha] 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 HNF4[alpha]. 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 HNF4[alpha] increases the expression of OCT1 and CNT3 in RCCNG1 cells, thereby increasing the chemosensitivity of tumor cells to oxaliplatin and 5-FU. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3326-3334, 2014 [PUBLICATION ABSTRACT]