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Page 144 Sendino et al. Cancer Drug Resist 2018;1:139-63 I http://dx.doi.org/10.20517/cdr.2018.09

XPO1 does not bind mRNA directly, NES-containing RNA-binding proteins that act as adaptors to bridge
[49]
the interaction between XPO1 and mRNA are essential in this process. These adaptors include NXF3 ,
[50]
[51]
and the HuR/APRIL/pp32 or the eIF4E/LRPPRC complexes. Interestingly, several mRNAs exported
by XPO1 code for proteins that are involved in tumorigenesis-related processes, such as invasion and
[46]
metastasis .
Finally, some RNA species with an important role in the regulation of gene expression (snRNA, lncRNA
and miRNA) can also be exported by XPO1 [52-54] . For example, although the major exporter of miRNAs is
not XPO1 but another exportin called XPO5, XPO1 mediated-export plays a role in the export and biogen-
esis of specific subsets of miRNAs [55,56] . Intriguingly, XPO1 has also been reported to mediate the nuclear
[57]
import of mature miRNAs .

Nuclear export-independent role of XPO1 as a key regulator of mitosis
Besides mediating the export of proteins and RNA to the cytoplasm, XPO1 also plays a role in processes that
do not directly involve nuclear export, such as intranuclear trafficking of small nucleolar RNAs (snoRNAs)
[58]
from Cajal bodies to the nucleolus . A particularly relevant aspect of cell physiology where XPO1 car-
[59]
[8]
ries out export-independent functions is mitosis . This role of XPO1 has been reviewed by Forbes et al. .
In eukaryotic cells undergoing open mitosis, the breakdown of the nuclear envelope at the onset of pro-
metaphase dramatically disrupts the nucleocytoplasmic compartmentalization. With no physical separa-
tion between nucleus and cytoplasm, the nuclear transport machinery, including certain transport recep-
tors, NUPs and the Ran GTPase, is “repurposed” to carry out transport-independent mitotic functions,
[59]
such as regulating the assembly of the mitotic spindle . In this context, XPO1 has been shown to function
as a “mitotic effector” of Ran, mediating RanGTP-dependent targeting of key mitotic proteins to specific
spindle structures, such as the centrosomes or the kinetochore. Thus, the NES-containing protein pericen-
trin, a crucial scaffold for microtubule nucleation at the spindle poles, is recruited to the centrosomes by
XPO1 in a RanGTP-containing trimeric complex that resembles the nuclear export complexes described
[60]
above . On the other hand, the stable microtubule-kinetochore interactions necessary for proper chromo-
some segregation appear to require XPO1-mediated recruitment of a protein complex containing RanGTP,
[8]
RanGAP1 and the nucleoporin RanBP2 to the kinetochores .
The mitotic functions of XPO1, like its nuclear export activity, seem to be the subject of careful regulation
[61]
[62]
through mechanisms that include phosphorylation and competition with importins .
In summary, although its primary role may be in protein nuclear export, XPO1 is a multifaceted protein
with roles in other processes. This functional complexity should be taken into account when interpreting
the results of XPO1 inhibition studies.

PATHOLOGICAL ALTERATION OF XPO1 IN CANCER
Altered nucleocytoplasmic localization of proteins in cancer
Normal cell function relies on the correct subcellular distribution of thousands of proteins. The presence
of a critical protein in the wrong cellular compartment may have severe pathological consequences. For
example, aberrant cytoplasmic localization of a physiologically nuclear tumor suppressor protein may ren-
der this protein inactive, and thus contribute to tumorigenesis. In fact, mislocalization of cancer-related
proteins, including the products of prominent oncogenes and tumor suppressor genes, has been often dem-
onstrated in human tumors [63,64-66] .

Nucleocytoplasmic localization of proteins can be disrupted by different mechanisms in cancer cells. On
one hand, the trafficking of a specific protein can be altered by mutations that either interfere with the ac-