The expression patterns of folate receptor (FR) isoforms, alpha and beta, in normal and malignant male and female reproductive tissues is described. The significance of the receptor in reproductive and developmental physiology is discussed. The potential value of the receptor expressed in malignant tissues including ovarian and endometrial cancers as a diagnostic marker and a therapeutic target is reviewed. Finally, the various transcriptional and post-transcriptional mechanisms that govern the tissue/tumor-specificity of the receptor and its regulation by folate and steroid receptor ligands are described; the potential value of this knowledge in developing better methods for the early detection and treatment of certain cancers is discussed.
The glycosyl-phosphatidylinositol anchored folate receptor (FR) mediates selective delivery of a broad range of experimental drugs to the receptor-rich tumors, but molecular mechanisms controlling FR internalization have not been adequately studied. FR quantitatively recycles between the cell surface and endocytic compartments via a Cdc42-dependent pinocytic pathway. Protein kinase C (PKC) activators including diacylglycerol and phorbol ester have previously been reported to increase the proportion of FR on the cell surface. Here we identify the alpha-subtype of PKC as the mediator of phorbol ester action on FR recycling and provide evidence that activated PKCalpha is recruited to FR-rich membrane microdomains where, in association with its receptor RACK1, it inhibits FR internalization; the activation state of Cdc42 remains unaltered. We also show that the PKC substrate, annexin II, is required for FR internalization. The studies clarify a molecular mechanism for the regulation of FR recycling through PKC which could potentially be exploited for effective drug delivery.
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