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Enhancement of Folate Receptor Expression in Tumor Cells Through the Glucocorticoid Receptor: A Promising Means to Improved Tumor Detection and Targeting

Department of Biochemistry and Cancer Biology, Medical College of Ohio, Toledo, Ohio

Requests for reprints: Monahar Ratnam, Department of Biochemistry and Cancer Biology, Medical College of Ohio, Toledo, OH 43614. Phone: 419-383-3862; E-mail: mratnam{at}mco.edu.

The utility of the folate receptor (FR) type , in a broad range of targeted therapies and as a diagnostic serum marker in cancer, is confounded by its variable tumor expression levels. FR-, its mRNA and its promoter activity were coordinately up-regulated by the glucocorticoid receptor (GR) agonist, dexamethasone. Optimal promoter activation which occurred at <50 nmol/L dexamethasone was inhibited by the GR antagonist, RU486, and was enhanced by coactivators, supporting GR mediation of the dexamethasone effect. The dexamethasone response of the FR- promoter progressed even after dexamethasone was withdrawn, but this delayed effect required prior de novo protein synthesis indicating an indirect regulation. The dexamethasone effect was mediated by the G/C-rich (Sp1 binding) element in the core P4 promoter and was optimal in the proper initiator context without associated changes in the complement of major Sp family proteins. Histone deacetylase (HDAC) inhibitors potentiated dexamethasone induction of FR- independent of changes in GR levels. Dexamethasone/HDAC inhibitor treatment did not cause de novo FR- expression in a variety of receptor-negative cells. In a murine HeLa cell tumor xenograft model, dexamethasone treatment increased both tumor-associated and serum FR-. The results support the concept of increasing FR- expression selectively in the receptor-positive tumors by brief treatment with a nontoxic dose of a GR agonist, alone or in combination with a well-tolerated HDAC inhibitor, to increase the efficacy of various FR-–dependent therapeutic and diagnostic applications. They also offer a new paradigm for cancer diagnosis and combination therapy that includes altering a marker or a target protein expression using general transcription modulators.

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				A. Shatnawi, T. Tran, and M. Ratnam R5020 and RU486 Act as Progesterone Receptor Agonists to Enhance Sp1/Sp4-Dependent Gene Transcription by an Indirect Mechanism Mol. Endocrinol., March 1, 2007; 21(3): 635 - 650. [Abstract] [Full Text] [PDF]