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

Publication Type:

Journal Article

Source:

The Journal of clinical investigation, Volume 121, Issue 8, p.3220-32 (2011)

Keywords:

Animalsdigestive disease, digestive deseases Antineoplastic Agentsdigestive disease, digestive deseases Apoptosisdigestive disease, digestive deseases Caco-2 Cellsdigestive disease, digestive deseases Cell Line, Tumordigestive disease, digestive deseases Cell Movementdigestive disease, digestive deseases Cell Proliferationdigestive disease, digestive deseases Colonic Neoplasmsdigestive disease, digestive deseases Fibroblast Growth Factorsdigestive disease, digestive deseases Humansdigestive disease, digestive deseases Micedigestive disease, digestive deseases Neoplasm Invasivenessdigestive disease, digestive deseases Neoplasm Metastasisdigestive disease, digestive deseases Neoplasm Transplantationdigestive disease, digestive deseases Phenotypedigestive disease, digestive deseases Plasmidsdigestive disease, digestive deseases Receptors, Steroid

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.