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New mechanisms of transcriptional regulation of the folate receptor and other genes by steroid Receptors

Year: 2007
Type: article
Abstract: The utility of the folate receptor (FR) type α, in a broad range of targeted therapies and as a diagnostic serum marker in cancer, is confounded by its variable tumor expression levels. FR-α, its mRNA and its promoter activity were coordinately up-regulated by the glucocorticoid receptor (GR) agonist, dexamethasone (Dex). Optimal promoter activation occurred at < 50 nM Dex, was inhibited by the GR antagonist, RU486, and was enhanced by co-activators, supporting GR mediation of the Dex effect. The Dex response of the FR-α promoter progressed even after Dex was withdrawn but this delayed effect required prior de novo protein synthesis indicating an indirect regulation. The Dex 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 Dex induction of FRα independent of changes in GR levels. Dex/HDAC inhibitor treatment, did not cause de novo FR-α expression in a variety of receptor-negative cells. In a murine HeLa cell tumor xenograft model, Dex treatment increased both tumor associated and serum FR-α. The results support the concept of increasing FR-α expression selectively in the receptorpositive tumors by brief treatment with a non-toxic dose of a GR agonist, alone or in combination with a well-tolerated HDAC inhibitor, to increase the efficacy of various FR-α-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.
Language: English
Subfield: Endocrinology
Open Access status: green
OpenAlex ID: W2195552492
FWCI:
Cites: 416
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Related to: 10