RESUMEN
BACKGROUND: The folate receptor is a 38 to 39 kd glycoprotein attached to the cell membrane via a glycosylphosphatidylinositol anchor. It serves as the initiation point for receptor-coupled transport of folate in a process known as potocytosis. The receptor is overproduced by a number of malignant cell lines in vitro and in a large percentage of ovarian and uterine malignancies. Immunohistochemistry has shown the receptor to be expressed primarily in normal differentiated tissues such as choroid plexus, placenta, thyroid, and kidney. The receptor gene(s) has been mapped to the human chromosomal locus 11q13. PURPOSE: In order to better understand regulation of the synthesis of the receptor, we studied the expression and accumulation of the folate receptor in UMSCC 38 cells, a human malignant squamous cell carcinoma line with a karyotype that is amplified at the folate receptor gene locus. METHODS: Western blot analysis of octylglucoside-solubilized cell membranes was used to analyze expression of several proteins by UMSCC 38 cells grown in culture under varied conditions. Bands on autoradiographs, representing electrophoresed proteins detected by indirect antibody labeling and an enhanced chemiluminescence reaction, were quantitated by densitometry. RESULTS: The expression of the folate receptor was found to increase approximately fourfold as UMSCC 38 cells were grown to higher cell densities over increasing lengths of time, ranging from 3 to 9 days, in culture. The expression of K1 keratin protein, a known marker of differentiation in squamous cell carcinomas, was elevated to a similar degree (3.2-fold) between day 5 and day 9 in cultures of these cells. Expression of folate-receptor protein in UMSCC 38 cells was also found to be reduced approximately 10-fold when cells were exposed to 1 microM retinoic acid for 48 hours and increased approximately eightfold after a 5-day exposure to 3 microM hydrocortisone. CONCLUSIONS: We present evidence that synthesis of the folate receptor in UMSCC 38 cells is affected by the same pathway that changes the expression of some markers of differentiation in squamous cell carcinomas. IMPLICATIONS: The fact that folate receptor expression in these malignant cells can be manipulated using retinoids and steroids suggests that these hormones could modulate the efficiency of folate and antifolate uptake via the folate receptor and may enhance the usefulness of the receptor as a target for immunotherapy.