Regulation of P -glycoprotein in the intestine during Xenopus laevis development and mammalian tumorigenesis

Abstract

In addition to being overexpressed in drug resistant tumors, P-glycoprotein is also present in specific normal tissues where it is proposed to detoxify organs. The high prevalence of P-glycoprotein in the intestinal epithelium is evolutionarily conserved from C. elegans to humans. The regulation of Xenopus laevis mdr (Xe-mdr) was examined during development. Expression of Xe-mdr was localized to the epithelial cells lining the intestinal tract and was first detected in the early tadpole stage prior to the onset of feeding, increased during intestinal development, then sharply declined during metamorphosis. In thyroid hormone-induced metamorphosis, a significant decrease in mdr message and protein was observed at a time in which the primary epithelium remained intact. Thyroid hormone also caused a reduction in mdr message in primary epithelial cell cultures. These results demonstrate that the Xe-mdr gene is developmentally regulated and suggest a role for thyroid hormone in this process.;The effect of thyroid hormone on mdr expression also was studied in a Xenopus epithelial cell line where thyroid hormone caused an increase in mdr message and P-glycoprotein. In mammalian cells, results from various studies including Northern blot analysis, triiodothyronine transport, cell growth, and cotransfection assays did not demonstrate a significant effect of thyroid hormone.;To determine the clinical implications of P-glycoprotein expression in the intestine, the changes in P-glycoprotein expression during intestinal tumorigenesis were studied in Apc1638 mice. These mice carry a mutation in the adenomatous polyposis coli gene and are predisposed to develop intestinal tumors. A similar mdr1a expression pattern was demonstrated along the cephalocaudal axis of the small intestine for wild type and Apc1638 mice. In Apc1638 mice, P-glycoprotein was highly expressed in the differentiated villus epithelium and barely detectable in the crypt stem cells. During early tumorigenesis, P-glycoprotein expression was decreased in the tumor epithelium compared to the adjacent villi. However, in advanced neoplasms, P-glycoprotein staining was prevalent at sites of invasion and in cells with the potential to become invasive. A similar P-glycoprotein distribution has been reported for human colon cancer, identifying the Apc1638 mouse model as an excellent system to study P-glycoprotein function during tumor progression in colon cancer.