Transferrin receptor 1: a target for antibody-mediated cancer therapy

The transferrin receptor 1 (TfR1), also known as CD71, is a homodimeric protein that is a key regulator of cellular iron homeostasis and proliferation [1,2]. It is a type II transmembrane protein with a large extracellular domain. This receptor interacts with iron-loaded transferrin (Tf) to import iron into the cell. The TfR1/Tf/iron complex is taken up through constitutive clathrin-mediated endocytosis. Due to the decrease in pH in intracellular vesicles, iron is released from Tf and the TfR1/Tf complex is recycled back to the cell surface where Tf dissociates from the receptor. Iron is a cofactor of intracellular enzymes including the ribonucleotide reductase that is coupled to DNA synthesis and, thus, required for cellular proliferation. Therefore, although TfR1 is expressed at a low level in a broad variety of cells, it is expressed at higher levels in rapidly proliferating cells, including malignant cells in which overexpression has been associated with poor prognosis [1,2]. Interestingly, TfR1 has also been shown to mediate NF-ĸB signaling in malignant cells through the interaction with the inhibitor of the NF-ĸB kinase (IKK) complex, increasing cancer cell survival [3]. Moreover, TfR1 can contribute to mitochondrial respiration and the production of reactive oxygen species (ROS), which play pivotal roles in tumor growth [4]. TfR1 overexpression on malignant cells and its central role in cancer cell pathology make it a meaningful target for antibody-mediated cancer therapy.

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