TY - JOUR
T1 - Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice
AU - Wang, Hongwei
AU - Venkatesh, Madhukumar
AU - Li, Hao
AU - Goetz, Regina
AU - Mukherjee, Subhajit
AU - Biswas, Arunima
AU - Zhu, Liang
AU - Kaubisch, Andreas
AU - Wang, Lei
AU - Pullman, James
AU - Whitney, Kathleen
AU - Kuro-o, Makoto
AU - Roig, Andres I.
AU - Shay, Jerry W.
AU - Mohammadi, Moosa
AU - Mani, Sridhar
PY - 2011/8/1
Y1 - 2011/8/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI41514
DO - 10.1172/JCI41514
M3 - Article
C2 - 21747170
AN - SCOPUS:79960980435
SN - 0021-9738
VL - 121
SP - 3220
EP - 3232
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -