Tumor-specific nuclear targeting: Promises for anti-cancer therapy?

Intracellular delivery as mediated by viruses and modular transporters. Viral particles such as that of adenovirus and modular transporters are able to interact specifically with a cell surface receptor (1), leading to receptor-mediated endocytosis (2). Certain viral and other proteins can undergo conformational modifications triggered by the acidic endosomal pH, causing disruption of the endosome (3) and the release of the viral particle or of the modular transporter into the cytoplasm so that they can subsequently be imported into the cell nucleus (4), where the genetic material is finally able to be expressed, or the drug released (5). PM, plasma membrane; NE, nuclear envelope; CT, cellular targeting, EE, endosomal escape; NT, nuclear targeting.

Schematic representation of nucleocytoplasmic transport. (A) Nuclear import occurs when IMPβ1, either alone or through IMPα, recognizes an NLS on the cargo protein in the cytoplasm (1) and mediates the docking of the complex to the NPC (2) followed by translocation into the cell nucleus. Binding of RanGTP to IMPβ1 (3) results in the cargo being released into the nucleus (4). (B) Nuclear export occurs when cellular export receptors, such as the IMPβ homologue CRM-1, recognize a NES on the cargo protein in the presence of RanGTP (1) and mediate the docking of the complex to the NPC and its translocation to the cytoplasm (2). Upon hydrolysis by Ran of GTP to GDP (3), facilitated by Ran GTPase-activating protein (not shown), the cargo is released into the cytoplasm (4).

Summary of the targeting sequences of VP3 and domains involved in protein–protein interaction. The single letter code is used for amino acid; NLS, nuclear localization signal; NES, nuclear export signal; PML, promyelocytic leukemia protein; Hippi, protein interactor of the Huntingtin interacting protein 1; APC1, subunit of the anaphase-promoting complex/cyclosome.

Model for VP3 tumor-specific nuclear localization. VP3 is recognized by IMPβ1 and transported into the nucleus in both normal and tumor cells (1). Once inside the nucleus, VP3 is released from IMPβ1 upon binding of RanGTP and localizes to the PML NBs (2). In tumor but not in normal cells, VP3 phosphorylation on T108 prevents recognition by CRM1 (3) and export to the cytoplasm (4). Thus, VP3 localizes more strongly in the nucleus in tumor rather than in normal cells, as illustrated in the confocal microscopic images of 1BR3 (normal; left) and 1BR3/N (transformed; right) cells expressing GFP-VP3 (lower panels); note that VP3 is, in fact, able to accumulate in the nuclei of non-tumor cells, but to a significantly reduced extent compared to in transformed cells (see ).