Folate Receptor Alpha (FRα) is a specific protein located on the surface of certain cells. It plays a significant role in binding and transporting folate, also known as Vitamin B9, into these cells. This protein’s presence and function are important for various cellular processes.
Folate and Its Receptors
Folate is a water-soluble B-vitamin essential for numerous bodily functions. It is involved in the synthesis and repair of DNA, the formation of red and white blood cells, and the conversion of food into energy. Folate is particularly important during periods of rapid cell division, such as during pregnancy and infancy, as it ensures the proper formation of genetic material.
Cells possess various mechanisms to absorb folate, including different types of folate receptors and transporters. Folate Receptor Alpha (FRα) is a specific mechanism that exhibits a high affinity for folate uptake. This high-affinity binding allows for efficient delivery of folate into the cell’s interior.
How Folate Receptor Alpha Functions
Folate Receptor Alpha (FRα) is a glycosylphosphatidylinositol (GPI)-anchored protein, meaning it is attached to the outer surface of the cell membrane. It has a high binding affinity for folate and its derivatives, including 5-methyltetrahydrofolate (5MTHF), which is the primary form of folate in circulation. This strong interaction allows FRα to efficiently capture folate from the extracellular environment.
FRα delivers folate into the cell via receptor-mediated endocytosis. After FRα binds to folate, the receptor-folate complex is internalized within a vesicle called an endosome. The environment within this endosome becomes slightly acidic, which causes a conformational change in the receptor, leading to the release of folate into the cell’s interior. The FRα receptor is then recycled back to the cell surface for further uptake.
Folate Receptor Alpha in Health and Illness
Folate Receptor Alpha (FRα) plays a dual role, participating in both healthy physiological processes and various disease states. In normal tissues, FRα expression is typically restricted to the apical surfaces of polarized epithelial cells, such as those found in the kidney, lung, and choroid plexus, where it is generally not exposed to the bloodstream. It is also found in the epithelial cells of the normal fallopian tube and placenta. FRα is involved in normal embryonic development and cell proliferation.
In contrast, FRα expression can be significantly altered in illness, particularly in various cancers. It is frequently overexpressed in certain malignancies, including ovarian, lung, breast, and kidney cancers, as well as endometrial and cervical cancers. This overexpression can be 10- to 100-fold higher in tumors, providing cancer cells with an increased supply of folate necessary for their rapid growth. Higher levels of FRα expression are correlated with advanced disease stages and recurrence in some solid tumors.
FRα also has involvement in specific neurological conditions, such as cerebral folate deficiency (CFD). In CFD, impaired FRα function can lead to reduced folate levels in the cerebrospinal fluid, despite normal folate levels elsewhere in the body. This can result from genetic mutations in the FOLR1 gene, which codes for FRα, or from autoantibodies that bind to and disrupt FRα function. Symptoms of CFD can include developmental delay, intellectual disability, seizures, and movement disorders, typically appearing between 5 and 24 months of age.
Therapeutic and Diagnostic Applications
Understanding Folate Receptor Alpha (FRα) has opened avenues for medical applications in both diagnostics and therapeutics. As a diagnostic tool, FRα can serve as a biomarker for certain diseases, particularly in detecting FRα-overexpressing tumors. Immunohistochemistry (IHC) assays are used to identify FRα expression in tumor tissue, helping determine eligibility for targeted therapies in patients with epithelial ovarian cancer. A high level of soluble FRα in serum has also been investigated as a noninvasive biomarker for ovarian cancer detection and prognosis.
In therapeutic strategies, FRα is targeted to deliver agents specifically to cancer cells. This approach leverages the overexpression of FRα on tumor cells. Folate-conjugated drugs, where folate acts as a targeting ligand, bind to FRα and are internalized via receptor-mediated endocytosis, allowing the drug to be released inside the cancer cell while minimizing side effects on healthy tissues. Immunotherapies, such as antibody-drug conjugates (ADCs) like mirvetuximab soravtansine and chimeric antigen receptor (CAR) T cells, are being developed or approved to target FRα-positive cancer cells. For neurological disorders like cerebral folate deficiency, treatment involves high doses of folinic acid, a form of folate that bypasses impaired FRα transport to reach the brain.