Speaker
Description
Double limitation characterizes the use of nuclear receptor (NR) modulation in cancer pharmacotherapy. First, it is approved in only few cancer entities. Second, it is restricted to a small number of NRs. In this study, we aimed to reveal the full potential of NRs as drug targets in anti-cancer therapy by combining bioinformatics, molecular biology and biochemical approaches.
Genome-wide gene expression and associated clinical data of The Cancer Genome Atlas were used to establish a scoring system for the pharmacotherapeutic potential of NRs in 18 cancer entities. Here, the highest number of NRs with a positive score was observed in clear cell renal cell carcinoma (n=485). Validation in our RCC biobank (n=140) confirmed the score for some of these NRs, including farnesoid X receptor (FXR, NR1H4), which additionally showed concordant effects in both cohorts. Thus, we investigated the FXR-dependent transcriptome in RPTEC/TERT1 renal cells by RNA sequencing. Gene ontology analyses revealed apoptotic pathway enrichment. Specifically, anti-apoptotic BCL2 was upregulated on mRNA and protein levels. Functionally, FXR activation resulted in protection from staurosporine-induced apoptosis, as shown by reduced caspase 3 activity and diminished proportion of apoptotic cells. Increased BCL2 expression was confirmed in renal tumor cell lines. Consequently, inhibition of FXR by siRNA-mediated knock-down and antagonists resulted in reduced proliferation.
In conclusion, our data suggest a pro-tumorigenic role of renal FXR and the potential usefulness of FXR inhibition in renal cancer therapy. More generally, they demonstrate the merit of our scoring system for identifying NRs with potential use in cancer pharmacotherapy.
