PXR: A stepping stone from environmental chemical to cancer?

by Biomechanics 

Several chemicals that can accumulate to high levels in our body (for example BPA and some pesticides) have been recently linked to an increased risk of cancer and/or impaired responsiveness to anticancer drugs.

A team of researchers, led by Sridhar Mani, at Albert Einstein College of Medicine, New York, has now identified a potential mechanistic link between environmental exposure to these foreign chemicals (xenogens) and cancer drug therapy response and survival.

PXR is one protein by which cells (including tumor cells) can sense xenogens. In their study, Mani and colleagues determined that activation of PXR was sufficient to enhance the cancerous characteristics of human colon tumor cell lines and primary human colon cancer tissue xenografted into immune system–deficient mice. Further analysis indicated FXR activation leads to colon cancer growth through the induction of the growth factor FGF19.

The authors therefore suggest that it will be important to investigate further the extent to which the environment might play a role in tumor recurrence through PXR activation.

PXR activation in colon cancer induces tumor growth that is inhibited by FGF19 inhibitory antibody.

Abstract From A Research Paper on PXR:

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.