Insulin-Degrading Enzyme, an Under-Estimated Potential Target to Treat Cancer?

Abstract

Insulin-degrading enzyme (IDE) is a multifunctional protease due to the variety of its substrates, its various cellular locations, its conservation between species and its many non-proteolytic functions. Numerous studies have successfully demonstrated its implication in two main therapeutic areas: metabolic and neuronal diseases. In recent years, several reports have underlined the overexpression of this enzyme in different cancers. Still, the exact role of IDE in the physiopathology of cancer remains to be elucidated. Known as the main enzyme responsible for the degradation of insulin, an essential growth factor for healthy cells and cancer cells, IDE has also been shown to behave like a chaperone and interact with the proteasome. The pharmacological modulation of IDE (siRNA, chemical compounds, etc.) has demonstrated interesting results in cancer models. All these results point towards IDE as a potential target in cancer. In this review, we will discuss evidence of links between IDE and cancer development or resistance, IDE's functions, catalytic or non-catalytic, in the context of cell proliferation, cancer development and the impact of the pharmacomodulation of IDE via cancer therapeutics.

Keywords: cancer; insulin-degrading enzyme; target.

Figure 1

Structure of IDE (from 4NXO). Catalytic site in black; Zn2⁺ ion in magenta; swinging door in olive exosite in cyan [19]; 20S proteasome binding in light blue [27]; E1 ligase-like activity important residue in green [29]; Ub-C-term binding in marine [28]; polyanion binding site in red [25]; cysteins sensitive to reactive oxygen species (ROS) or reactive nitrogen species (RNS) in yellow spheres [30].

Figure 2

(a) Condensed representation of the insulin and IGF pathways. After ligand binding and activation, insulin and IGF1 receptors induce a signal through IRS via MAPK and AKT pathways to control cell metabolism and survival. IGFBP proteins bind IGFs and reduce their signals. The binding of IGF2 to IGF2-R leads to internalization and lysosomal degradation. (b) IDE is involved in insulin clearance, particularly in endosomes, after activating insulin receptors by its ligand. (c) Cancer cells overexpress insulin and IGF1 receptors. Cancer cells can produce IGF proteins that act in an autocrine and paracrine manner. Insulin and IGF pathways contribute to cancer development. Red arrows mean overexpression. Created with BioRender.com (accessed on 31 March 2022).

Figure 3

Impact of the environment on cancer cells that could involve IDE modulation as a response. Cancer cells are submitted to various stresses such as oxidative, metabolic, heat, hypoxia, proteotoxic stresses, inflammation and immune recognition that induce a response that can allow cell survival or death. It is known that IDE can modulate or be modulated by these different stresses. Created with BioRender.com (31 March 2022).

Figure 4

Potential IDE involvement in some cancer hallmarks by its substrates, its protein-protein interactions or by itself with its modulations. The main effect of substrates is reported and can act positively or negatively on cancer hallmarks (Table 1). Created with BioRender.com (31 March 2022).