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Degree

Doctor of Philosophy in Medical Sciences (Ph.D.), University of Toledo Health Science Campus, Graduate School, 2005.

Abstract

Folate receptor (FR) is a GPI-anchored cell surface protein. Three iso-forms of FR have been identified and characterized, FRa, FRb and FRg/FRg’. Folate receptor is capable of transporting folate/antifolate compounds and folate conjugates into the cell functions in transport of folates into the cell. Folate receptor a is found on certain normal epithelial cells and highly expressed in various cancer tissues including non-mucinous ovarian cancers, uterine endometrial endometrioid adenocarcinoma, ependynomas, menigioma and some colon and breast cancers. In normal tissues, FRa is restricted on the apical (luminal) aspect of the polarized epithelial cells, thus rendering it inaccessible through the circulation. However, it is accessible through the circulation in malignant tissues owing to the hypervascularization seen in these tissues. Folate compounds or conjugates can be effectively taken up into the cell by means of FRa due to its ability to shuttle back and forth between the cell membrane and endosomal compartment. Folate receptor mediated targeting has been shown to be highly specific and effective and dependent on the density of FR on the cell membrane. However, the expression of FR in tumors is highly variable among tumors of certain type and heterogeneous within a tumor. Therefore, an optimal expression of FR in malignant tissues will help optimize the effectiveness of FR-mediated targeting. We have found that both in cell culture and in tumor xenograft mouse model, Dexamethasone (Dex) can up-regulate the FRa gene in Hela cells and this is significantly enhanced when either valproic acid (VPA) or trichostatin A (TSA), both HDAC inhibitors, is used in conjunction with Dex. In addition, in Hela cells co-transfected with a FRa promoter luciferase construct and an expression vector for either PRa or PRb, the progestin R5020 can up-regulate the FRa promoter up to ten-fold. Furthermore, in non-responsive cells such as T47D, co-treatment of R5020 with TSA can up-regulate the expression of the FRa promoter. Our findings establish the usefulness of employing Dex, R5020 and HDAC inhibitors to up-regulate FRa in order to improve FRa-mediated targeting. We report mechanistic aspects of the regulation of FRa by progestins and glucocorticoids that are relevant for its utility as a tumor target.

Subject Headings

Biology, Molecular

Keywords

folate receptor; glucocorticoid receptor; progesterone receptor

Advisor

Manohar Ratnam

Pages

293p.

Document number: mco1104777244
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=mco1104777244

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