Targeting the Transferrin Receptor to Overcome Resistance to Anti-Cancer Agents

Abstract

The transferrin receptor (TfR) plays an important role in iron uptake and delivery [1]. The primary role of the TfR is to internalize iron through the binding of its natural ligand, the transferrin (Tf) protein that carries iron through the circulation. Iron is necessary for various cell processes such as respiration, metabolism, DNA synthesis and the proper functioning of various heme and nonheme proteins that require iron as a cofactor [1]. In addition, the TfR seems to be important for other processes such as cell growth and proliferation [1]. The TfR, a 180-kDa homodimeric glycoprotein, is a type II transmembrane receptor that has three important domains for its function (Fig. 2.1). It is composed of a C-terminal domain, also known as the ectodomain, a transmembrane region, and an N-terminal domain that is on the cytosolic side of the membrane. The ectodomain is important for binding to Tf for the internalization of iron. Two TfR genes have been identified, TfR1 and TfR2. Furthermore, the TfR2 gene produces two transcripts, α and β, that are produced by alternative splicing. TfR2α shows similarity with TfR1 in that they exhibit a 45% similarity and 66% homology in their ectodomain. However, the cytoplasmic domains of the two proteins demonstrate no similarity [1]. The TfR2β transcript lacks the transmembrane and cytoplasmic domains and its function remains unknown. TfR1 and TfR2α differ in cell surface expression and gene regulation. The TfR1 is ubiquitously expressed on normal cells at low levels. Increased TfR1 expression is observed on cells with a high proliferation rate, including cancer cells. TfR2 expression is limited to hepatocytes and enterocytes in the small intestine [1]. TfR2 expression has been found in some human cell lines such as B and myeloid cell lines as well as some cell lines derived from solid tumors [1]. TfR1 is post-transcriptionally regulated directly by intracellular iron levels as compared with TfR2 that is not. TfR2 is thought to be primarily regulated by the cell cycle and iron-bound Tf [1]. Thus both receptors differ considerably in expression and regulation indicating different roles in iron delivery. In addition, TfR1 has a 25-fold greater affinity for Tf relative to TfR2, indicating the main role of TfR1 in iron homeostasis [1]. Tf is an 80 kDa monomeric glycoprotein composed of two lobes; an N and C lobe that are separated by a short spacer sequence (reviewed in [1]). Each lobe is capable of binding one iron molecule. The number of iron molecules bound to Tf has an important effect on the affinity of Tf for the TfR. At physiological conditions, holo Tf or diferric Tf (two iron) has the greatest affinity followed by monoferric (one iron), while apo-Tf (no iron) has the lowest affinity for the receptor [1]. Thus, iron uptake by the cell is mediated mostly through the Chapter 2 Targeting the Transferrin Receptor to Overcome Resistance to Anti-Cancer Agents