Decades of clinical research in patients with solid tumors have demonstrated that complete and durable tumor regressions are rare. Indeed the clinical experience with chemotherapy for most solid tumor malignancies indicates that dose-escalation or high-dose chemotherapy does not result in an improvement in patient progression-free or overall survival (1
). The classical theories that explain this apparent lack of benefit posit the existence of drug-resistant tumor stem cells and/or intrinsic and/or induced tumor cell resistance. These cells eventually regrow within the tumor bed or at distant metastatic sites (5
One tumor pathway that may allow for these cells to sense, and respond to, xenochemicals is signaling via the xenobiotic nuclear receptors (e.g., pregnane X receptor/SXR [PXR/SXR], CAR, LXR, farnesol X receptor [FXR], VDR) (8
). A receptor in this family, the PXR (also known as SXR, PAR, PRR, or NR1I2), is unique in that it is activated by a diverse array of xenochemicals, including chemotherapies (e.g., paclitaxel, tamoxifen) and naturally occurring endocrine disruptors (e.g., bisphenol A, organochlorine pesticides, methoxychlor, and benzophenone) (9
). This promiscuous xenosensor plays a central role in regulating liver and gastrointestinal drug metabolism. However, PXR is widely expressed in many different tissues and tumors (e.g., colon, breast, and ovary) (15
). In search of tissue-specific functions of PXR, we previously demonstrated that PXR activation induces ovarian cancer cell proliferation and drug resistance (20
). While several molecular mechanisms promote this phenotype, recent work indicated that, like the FXR, PXR might also regulate FGF19 expressions in the intestines (21
). The importance of this observation with regards to cancer is that FGF19 transgenic mice develop hepatocellular carcinoma, and abrogation of FGF19 signaling inhibits colon cancer xenograft growth (24
). FGF19, FGF21, and FGF23 comprise the endocrine-acting branch of FGF family, which requires α/βklotho coreceptors to activate their cognate FGF receptors (FGFRs). FGF19 signals mainly through FGFR4 in a βklotho-dependent fashion and induces multiple intracellular pathways, including MAPK and STATs (25
). Unlike FGF21 and FGF23, which are strictly coreceptor dependent, FGF19 has also the ability to activate FGFR4 in the absence of βklotho. Indeed, FGFR4 expression has been tied to cancer growth and drug resistance (25
A more controversial area of research is the extent to which environmental xenotoxins play a role in determining human cancer outcomes. Since incurable cancer, which afflicts over 450 persons per 100,000 annually, is a growing health epidemic, it is important to establish a relationship between environmental xenogens (i.e., endocrine disruptors) and cancer (30
). Indeed, recent studies on this subject indicate a growing correlation between high exposure to endocrine disruptors (e.g., bisphenol A, xenoestrogens, polycyclic aromatic hydrocarbons) and cancer risk or drug response (13
). The question is particularly relevant given that recent developments in cancer drug therapy (e.g., targeted therapy) are markedly improving survivability. Simultaneously, over the last several decades, our burden of environmental xenotoxins has increased substantially. Recent work implicates several xenogens in cancer cell growth and drug resistance (13
). Indeed, the molecular pathways governing the tissue-specific phenotypes mediated by chronic exposure to endocrine disruptors are varied, and it is clear that some important effects are mediated via nuclear receptors.
In the current study, we tested the link between PXR-mediated tumor cell growth and the regulation of FGF signaling. Specifically, we show that PXR regulated FGF19 expression in colon cancer cells but not in intestinal crypt cells through direct repeat 3–specific (DR3-specific) transcriptional activation of the FGF19 promoter. Strategies to ablate FGF19 signaling prevented PXR-mediated colon tumor growth. Our results have far reaching implications that may mechanistically tie environmental xenogen exposure with cancer drug therapy response and survival.