Targeting nucleocytoplasmic transport in cancer therapy

Abstract

The intracellular location and regulation of proteins within each cell is critically important and is typically deregulated in disease especially cancer. The clinical hypothesis for inhibiting the nucleo-cytoplasmic transport is based on the dependence of certain key proteins within malignant cells. This includes a host of well-characterized tumor suppressor and oncoproteins that require specific localization for their function. This aberrant localization of tumour suppressors and oncoproteins results in their their respective inactivation or over-activation. This incorrect localization occurs actively via the nuclear pore complex that spans the nuclear envelope and is mediated by transport receptors. Accordingly, given the significant need for novel, specific disease treatments, the nuclear envelope and the nuclear transport machinery have emerged as a rational therapeutic target in oncology to restore physiological nucleus/cytoplasmic homeostasis. Recent evidence suggests that this approach might be of substantial therapeutic use. This review summarizes the mechanisms of nucleo-cytoplasmic transport, its role in cancer biology and the therapeutic potential of targeting this critical cellular process.

Figure 1. Potential therapeutic targets at different level of the nucleo-cytoplasmic transport process

Therapeutic agents such as small molecules or biologics targeting nucleo-cytoplasmic transport of oncoproteins or tumor suppressor proteins can interfere with upstream regulatory components (I), the interaction between cargo proteins and the transport receptors (II), the interaction between the transport receptors and the Ran regulators (III) and the NPC (IV).

Figure 2. The subcellular distribution of oncogenes and tumor suppressors in normal cells and their redistribution following transformation

A schematic indicating the subcellular localization of key protein in normal (left hand side) and cancer cells (right hand side). Transport receptors (TR) are broadly indicated within normal cells however we highlight specifc nuclear import/export proteins and indicate specifc agents (numbered 1-26 and listed in Table 2) that can target the aberrant protein localization within a number of cancers. As can be seen in the fgure, signifcant components of these aberrant pathways (particularly Ras, Rb and β-catenin subcellular localization) have yet to be targeted