Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential

Abstract

The Karyopherin superfamily is a major class of soluble transport receptors consisting of both import and export proteins. The trafficking of proteins involved in transcription, cell signalling and cell cycle regulation among other functions across the nuclear membrane is essential for normal cellular functioning. However, in cancer cells, the altered expression or localization of nuclear transporters as well as the disruption of endogenous nuclear transport inhibitors are some ways in which the Karyopherin proteins are dysregulated. The value of nuclear transporters in the diagnosis, prognosis and treatment of cancer is currently being elucidated with recent studies highlighting their potential as biomarkers and therapeutic targets. V C 2016 IUBMB Life, 68(4): [268][269][270][271][272][273][274][275][276][277][278][279][280] 2016

Importin-β and CRM1 control a RANBP2 spatiotemporal switch essential for mitotic kinetochore function

“…Of note, several cancer types overexpress these karyopherins (Rensen et al, 2008;van der Watt et al, 2009) and inhibitors of nuclear transport processes are being developed with therapeutic purposes (Stelma et al, 2016;Mahipal and Malafa, 2016). The present data suggest that the relative abundance of importin-β and CRM1 is crucial to KT functions that depend on the RRSU complex.…”

Confinement hinders motility by inducing RhoA-mediated nuclear influx, volume expansion, and blebbing

“…Interestingly, inhibitors of nuclear export have shown promising preclinical results and are currently being evaluated in clinical trials as tumor suppressors. Although these results are primarily attributed to the reduction of tumor growth (Stelma et al, 2016), we suggest that these inhibitors may also disrupt nuclear integrity and interfere with metastatic spread due to increased nuclear size and concomitant decreased cell migration/invasion.…”

Peptide Bond Cleavage by Ni(II) Ions within the Nuclear Localization Signal Sequence

“…Both events may disrupt the transport of the protein to the nucleus, the first one reversibly, and the second irreversibly. Dysfunction of nuclear transport occurs in some diseases, including several types of cancer . Furthermore, as some of the NLSs are localized between different domains of the proteins, the alteration or destruction of this fragment may deteriorate other physiological functions of the affected biomolecules.…”