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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 Article has an altmetric score of 3

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

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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 1

PXR activation induces cell proliferation and cell migration in vitro and in vivo.

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PXR activation induces cell proliferation and cell migration in vitro an...
(A) Proliferation of LS174T cells expressing either scrambled shRNA or PXR shRNA in response to different concentrations of rifampicin (0–50 μM). (B) Tumor volumes (C) and tumor weights of xenografts of LS174T cells expressing either PXR shRNA or scrambled shRNA (n = 12 per group; day 42). (D) Transwell migration assay performed in the presence or absence of rifampicin (25 μM) or EGF (5 nM). (E) Representative photograph of a spleen-liver pair from a single typical mouse sacrificed on day 14 after intrasplenic inoculation with LS174T cells. There is a 100% metastasis rate to the liver (n = 8 mice; data not shown). The black arrows indicate tumor nodules. (F) Histogram depicts mean gross tumor count on the surface of the liver in 48 mice (n = 12 per group). (G) H&E stain and microscopic examination (scale bar: 200 μm [left panel]; 50 μm [right panel]) of tumor nodules in a mouse liver. The black arrow represents a tumor nodule. (H) Histogram depicts mean microscopic tumor count on the surface of the liver obtained from F. (A and D) n = 4 in triplicate. DMSO (0.2%) was the vehicle for all in vitro experiments. Data are presented as mean ± SEM. *P < 0.001, **P < 0.01, #P < 0.001, ##P < 0.001, ###P < 0.001, comparing the 2 groups as indicated. Rif, rifampicin.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 3 patents
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