title: Modulation of expression of the nuclear receptor NR0B2 (small heterodimer partner 1) and its impact on proliferation of renal carcinoma cells.
abstract: Mammalian nuclear receptors (NRs) are transcription factors regulating the expression of target genes that play an important role in drug metabolism, transport, and cellular signaling pathways. The orphan and structurally unique receptor small heterodimer partner 1 (syn NR0B2) is not only known for its modulation of drug response, but has also been reported to be involved in hepatocellular carcinogenesis. Indeed, previous studies show that NR0B2 is downregulated in human hepatocellular carcinoma, suggesting that NR0B2 acts as a tumor suppressor via inhibition of cellular growth and activation of apoptosis in this tumor entity. The aim of our study was to elucidate whether NR0B2 may also play a role in other tumor entities. Comparing NR0B2 expression in renal cell carcinoma and adjacent nonmalignant transformed tissue revealed significant downregulation in vivo. Additionally, the impact of heterologous expression of NR0B2 on cell cycle progression and proliferation in cells of renal origin was characterized. Monitoring fluorescence intensity of resazurin turnover in RCC-EW cells revealed no significant differences in metabolic activity in the presence of NR0B2. However, there was a significant decrease of cellular proliferation in cells overexpressing this NR, and NR0B2 was more efficient than currently used antiproliferative agents. Furthermore, flow cytometry analysis showed that heterologous overexpression of NR0B2 significantly reduced the amount of cells passing the G1 phase, while on the other hand, more cells in S/G2 phase were detected. Taken together, our data suggest that downregulation of NR0B2 may also play a role in renal cell carcinoma development and progression.
authors.affiliation: Department of Pharmaceutical Sciences, Biopharmacy, University of Basel, Basel, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Prestin
authors.affiliation: Center of Drug Absorption and Transport, Institute of Pharmacology.
authors.forename: Maria
authors.initials: M
authors.lastname: Olbert
authors.affiliation: Department of Pharmaceutical Sciences, Biopharmacy, University of Basel, Basel, Switzerland.
authors.forename: Janine
authors.initials: J
authors.lastname: Hussner
authors.affiliation: Department of Pharmaceutical Sciences, Biopharmacy, University of Basel, Basel, Switzerland.
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Isenegger
authors.affiliation: Department of Pharmaceutical Sciences, Biopharmacy, University of Basel, Basel, Switzerland.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Gliesche
authors.affiliation: Center of Drug Absorption and Transport, Institute of Pharmacology.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Böttcher
authors.affiliation: Department of Urology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Zimmermann
authors.affiliation: Department of Pharmaceutical Sciences, Biopharmacy, University of Basel, Basel, Switzerland.
authors.forename: Henriette E
authors.initials: HE
authors.lastname: Meyer Zu Schwabedissen
keywords: NR0B2; SHP1; kidney cancer; nuclear receptor; proliferation; small heterodimer partner