Inhibiting cancer cell hallmark features through nuclear export inhibition

Abstract

Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. Nuclear export factor chromosomal region maintenance 1 (CRM1; Xpo1 and exportin-1) controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials (phase I-III) on both advanced-stage solid and hematological tumors. In this review, we compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy.

Figure 1

An overview of nucleocytoplasmic transport. Nucleocytoplasmic transport requires cargo with accessible NES or NLS, and its corresponding transport factor exportin or importin. For simplicity, bidirectional keryopherin-mediated transport is omitted. GAP, GTPase-activating protein; NEI, nuclear export inhibitor; NES, nuclear export signal; NLS, nuclear import signal; NPC, nuclear pore complex; RanGDP and RanGTP, GDP- and GTP-bound form of the small GTPase protein Ran.

Figure 2

CRM1-mediated nuclear export and cancer hallmarks. CRM1 contributes to the different aspects of cancer hallmarks and CRM1 inhibition may downregulate 9 out of 10 cancer hallmark processes simultaneously. Proteins in black are direct cargoes of CRM1, which are mislocalized to the cytoplasm in various cancer cells. Proteins in red may not be direct cargoes of CRM1, but are shown to be suppressed by nuclear export inhibition through different mechanisms.

Figure 3

Four classes of nuclear export inhibitors (NEIs). Two representative NEIs from each class is drawn, including (a) bacterial products leptomycin B and ratjadone A; (b) plant ingredients goniothalamin and plumbagin; (c) wortmannin from fungus and 15d-PGJ2 from animals; (d) synthetic NEIs CBS9106 and KPT-330. Asterisk (*) denotes possible covalent binding sites to Cys528 on CRM1.

Figure 4

Binding of CRM1 by different molecules. CRM1’s NES-binding grove in the empty (a), NES-bound (b), leptomycin B-bound (c) and KPT-185-bound (d) states is shown in green surface representation. The pdb codes are 4HB2, 3GB8, 4HAT and 4GMX respectively. Cys528 is highlighted in purple. NES, LMB and KPT-185 are colored yellow, tint and brown respectively. Three aligned residues are colored cyan to illustrate the orientation of NES groove. (e) Mechanism of LMB conjugation. R resembles the long polyketide chain. (f) Mechanism of KPT-185 conjugation.