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.
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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

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Figure 2

LS174T cell proliferation and migration in response to PXR activation are mediated by induction of FGF19 expression.

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LS174T cell proliferation and migration in response to PXR activation ar...
(A) Real-time quantitative PCR (QPCR) of FGF19 and MDR1 in LS174T cells expressing either scrambled shRNA or PXR shRNA (stimulated with either rifampicin [10 μM] or vehicle). Gene expression changes were calculated using comparative Ct method, with β-actin as the reference gene and scrambled shRNA plus vehicle as the calibrator. (B) Representative immunoblot analysis of FGF19 from LS174T cells (as in A) exposed to rifampicin (10 μM) or vehicle, with β-actin as loading control. Absolute band intensity (ImageJ; http://rsbweb.nih.gov/ij/) is plotted as a function of lanes from immunoblots. (C) Proliferation of LS174T cells exposed to rifampicin (0–50 μM), FGF23 inhibitor (400 ng/ml), and FGF19 inhibitor (400 ng/ml) as illustrated. (D) Transwell migration assay in the presence or absence of rifampicin (25 μM) or vehicle alone or in combination with FGF19 inhibitor (400 ng/ml) or FGF23 inhibitor (400 ng/ml). (E) Proliferation of LS174T cells that had been stimulated with FGF19 protein (1,000 ng/ml), with or without FGF19 inhibitor (400 ng/ml) or FGF23 inhibitor (400 ng/ml). (F) Transwell migration assay performed with LS174T cells stimulated with rifampicin (25 μM) or vehicle alone or in combination with FGF19 inhibitor (400 ng/ml) and FGF23 inhibitor (400 ng/ml) as illustrated. Data are presented as mean ± SEM. (A and C–F) n = 4 in triplicate; (B) n = 3. DMSO (0.2%) was the vehicle for all in vitro experiments. #P < 0.001, *P < 0.001, **P < 0.001, ***P < 0.001.