Artikel
Folate receptor processing and localization as oncological markers and therapeutic targets in prostate cancer
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Veröffentlicht: | 26. März 2024 |
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Gliederung
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Introduction: Folate receptors (FR) are already known as a selective entry site into cancer cells in various therapeutic approaches. Due to the proliferation-induced high demand of cancer cells for folic acid (FA), significant overexpression of FR1 is detected in most cancers. Also, diagnostically, this overexpression can be used as a suitable marker for different cancers. Overexpression of glycosylphosphatidylinositol-transamidase (GPI-T), which is responsible for the localization of membrane-bound proteins like FR1 in lipid rafts, is also associated with an increased risk of progression or metastasis in a variety of carcinomas. To our knowledge, a detailed characterization of FR1- and GPI-T- expression patterns and regulation regarding therapeutic and diagnostic feasibilities in PCa has yet to be described.
Methods: Cell culture studies and tissue sections of different PCa patients were analyzed by western blot, qRT-PCR and immunofluorescence, characterized by cellular fluorescence intensity and localization analysis. In addition, we utilized FA-functionalized lipoplexes to characterize the potential of FR1-targeted delivery into PCa cells.
Results: Interestingly, we detected high levels of FR1-mRNA in healthy prostate epithelial cells and comparably high protein levels in healthy prostate tissue. In prostate cancer cells however, we were able to show that in vitro early stages of hyperplastic alteration in prostate tissue (PIN-HG) and PCa show a massive enhanced FR1-membrane-localization where the receptor can finally gain its function. We were able to link these changes to the overexpression of GPI-T by image analysis. PCa cells in vitro and cancer tissue show GPI-T’s most potent overexpression, thereby inducing FR1 membrane localization. Finally, we utilize FA-functionalized lipoplexes to selectively transfer DNA into PCa-cells to evaluate a potential therapeutic value of the discovered mechanisms.
Conclusions: Thus, FR1 represents a promising candidate for targeted therapeutic transfer pathways in PCa and, in combination with GPI-T, may provide predictive imaging and established diagnostics.