Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice
Hongwei Wang, … , Moosa Mohammadi, Sridhar Mani
Hongwei Wang, … , Moosa Mohammadi, Sridhar Mani
Published July 11, 2011
Citation Information: J Clin Invest. 2011;121(8):3220-3232. https://doi.org/10.1172/JCI41514.
View: Text | PDF
Research Article Oncology

Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice

Abstract

The nuclear receptor pregnane X receptor (PXR) is activated by a range of xenochemicals, including chemotherapeutic drugs, and has been suggested to play a role in the development of tumor cell resistance to anticancer drugs. PXR also has been implicated as a regulator of the growth and apoptosis of colon tumors. Here, we have used a xenograft model of colon cancer to define a molecular mechanism that might underlie PXR-driven colon tumor growth and malignancy. Activation of PXR was found to be sufficient to enhance the neoplastic characteristics, including cell growth, invasion, and metastasis, of both human colon tumor cell lines and primary human colon cancer tissue xenografted into immunodeficient mice. Furthermore, we were able to show that this PXR-mediated phenotype required FGF19 signaling. PXR bound to the FGF19 promoter in both human colon tumor cells and “normal” intestinal crypt cells. However, while both cell types proliferated in response to PXR ligands, the FGF19 promoter was activated by PXR only in cancer cells. Taken together, these data indicate that colon cancer growth in the presence of a specific PXR ligand results from tumor-specific induction of FGF19. These observations may lead to improved therapeutic regimens for colon carcinomas.

Authors

Hongwei Wang, Madhukumar Venkatesh, Hao Li, Regina Goetz, Subhajit Mukherjee, Arunima Biswas, Liang Zhu, Andreas Kaubisch, Lei Wang, James Pullman, Kathleen Whitney, Makoto Kuro-o, Andres I. Roig, Jerry W. Shay, Moosa Mohammadi, Sridhar Mani

×

Figure 7

PXR binds to the endogenous FGF19 promoter and recruits RNA Pol II in LS174T cells.

Options: View larger image (or click on image) Download as PowerPoint
PXR binds to the endogenous FGF19 promoter and recruits RNA Pol II in LS...
ChIP analysis of PXR in (A) HIEC-PXR and (B) LS174T cells. The ChIP analysis was performed 5 separate times (each time in duplicate) for QPCR and plotted as a signal ratio between the PXR and IgG lane (FGF19) as illustrated. (C) Pol II bound to endogenous FGF19 promoter in LS174T cells and HIECs overexpressing PXR (HIEC-PXR). (D) XhoI chromatin accessibility assay by real-time PCR (CHART-QPCR) was performed using cell nuclei from rifampicin- or vehicle-treated LS174T and HIEC-PXR cells (for primer sequence details, see Supplemental Table 1). The nuclei were treated with XhoI for 30 to 120 minutes. The XhoI accessibility was expressed as a percentage of the uncut DNA and is plotted against the time of XhoI digestion. All experiments were repeated at least 3 independent times, each in triplicate. CHART-QPCR assays were performed 4 independent times, with 6 repeats per assay point. (E) PXR transactivation assay was performed in LS174T cells and HIECs using the –2,216-bp FGF19 reporter (n = 3 in triplicate). (F) The PXR transactivation assay was performed in LS174T cells and HIECs using FGF19 promoter (–2,216-bp) wild-type, DR3 mutant, and/or ER6 mutant reporter constructs (n = 3 in triplicate). Data are presented as mean ± SEM (± SD is shown for ChIP QPCR data). DMSO (0.2%) was the vehicle for all in vitro experiments. “2.4x” indicates a 2.4 fold change compared with that of vehicle.