Definition

Folate receptor 1 (folate receptor alpha, FRalpha, FRα, FOLR1, NCFTD) is a protein encoded by the FOLR1 gene in humans. There are three receptors that transport folate in the human body, and the Folate receptors (FRs) are one of them. The folate receptor family has four subtypes, FRα, FRβ, FRγ and FRδ, encoded by FOLR1, FOLR2, FOLR3 and FOLR4, respectively. With a size of 38-45 kDa, the protein family’s homology is about 70%. Among them, FRα is overexpressed in a variety of cancers, especially ovarian cancer, and makes it an ideal anti-tumor target due to its differentiated expression in normal and cancer tissues. Although the expression level of folic acid receptor FRα in different types of tumors is slightly different, in almost all ovarian cancer and most malignant tumors such as breast cancer, cervical cancer, colon cancer, rectal cancer, nasopharyngeal cancer, etc., folic acid receptor can almost produce a role. Some tumor tissues even with expression rate of more than 90%, the use of folic acid receptor in tumor tissue high expression, and in normal tissue rarely expressed, the characteristics of low toxicity to normal tissue, folic acid or folic acid analogues as a carrier, radionuclides, Antitumor drugs and gene drugs are coupled with them, which can effectively achieve targeted delivery of drugs and play a role in the diagnosis and treatment of diseases.

Fig. 1 Crystallographic structure of FRα protein. From the Protein Data Band (4LRH). The folate is in green, the

folate binding site is colored in orange. The Cys66Tyr substitution position induced by the pathogenic variant

described in our case report is represented in red while the disulfide bond between Cys66 and Cys109 is in dark blue.

-- Folate binds to FRα and mediates JAK-dependent processes through GP130 coreceptors, inducing STAT3 activation.

-- FOLR1 may form macromolecular complexes with LYN tyrosine kinase, which regulates phosphorylation of PEAK1, thereby promoting ERK and STAT3 activation.

-- GPI-anchored FOLR1 internalized in small vesicles to form early endosomes, which undergo acidification and subsequent fusion with lysosomes to release FOLR1 and folate. FOLR1 is then transferred to the nucleus and acts directly as a transcription factor.

-- FOLR1 acts as a folate transporter, and rapidly proliferating cells need to ingest enough folate for single-carbon metabolic reactions and DNA synthesis, repair and methylation.

Fig.2 Mechanism of the FOLR1 Signaling Pathway

Function

The receptor is responsible for binding to folic acid and its derivatives, which becomes crucial during fetal development. By supplementing with folic acid during pregnancy, neural tube defects in the fetus can be prevented. Folate derivatives are required for important metabolic processes such as DNA, protein, and lipid methylation. What's more, folic acid plays an important role in DNA replication and cell division, a common feature of rapid growth. Without proper folate levels, neural tube defects can occur. Neural tube defects are when the neural tube is underdeveloped because it is not properly sealed. This can lead to anencephaly or spina bifida, two neurological abnormalities.

Folate receptor α (FRα) is a potent target for anticancer drugs. It includes limited expression in non-malignant tissues, combined with overexpression in malignant tissues of some cancers, making FRα potentially a target using multiple platforms, such as antibodies, antibody-drug conjugates (ADCs), bispecific antibodies, or chimeric antigen receptor (CAR) T cells. Studies have shown that the proportion of FRα overexpressed in non-small cell lung cancer, mesothelioma, endometrial cancer and epithelial ovarian cancer is about 14~74%, 72~100%, 20~50% and 76~89%, respectively. In most ovarian cancers, folate receptor α (FRα) is overexpressed, so targeted FRα therapy is extremely promising.

Clinical Application

Due to its high expression in some tumors, FOLR1 is an attractive therapeutic target for the development of novel anticancer drugs to limit toxic side effects on non-target tissues. FOLR1 is overexpressed in many epithelial-derived tumors, including ovarian, breast, kidney, lung, colorectal, and brain cancers.

Folate receptor in normal tissues is not expressed or low expression, but in some tumor tissues highly expressed, and the affinity is higher, using this property, imaging agents, therapeutic drugs, etc. can be coupled with folic acid, targeted to tumor cells, so as to be used in tumor imaging diagnosis and tumor treatment. Autoantibodies to FOLR1 have been implicated in neurodevelopmental disorders, particularly folate deficiency, schizophrenia, and autism spectrum disorders. These neurodevelopmental disorders can be treated with folic acid.

Alpha Lifetech Inc. is dedicated to developing Folate receptor 1 diagnostic regents. Alpha Lifetech Inc. is a reputable supplier focusing on research, manufacture and sales of In Vitro Diagnostic (IVD) regents. All the IVD regents offered by Alpha Lifetech Inc. have undergone strict QC validation and are certified by the COA (certificate of analysis). Meanwhile, we can provide customized services according to customers' requirements. Alpha Lifetech Inc. is committed to supplying high-quality, high-sensitivity antigen and antibody products for scientific research and industrial customers. In addition to regular small packages, Alpha Lifetech Inc.'s large-scale fermentation platform also allows us to provide raw material-grade IVD regents for the majority of industrial customers.

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