Ran in Mitosis - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 135

served as markers for transformed cells in several cancer models. Malignancy was
correlated with the levels of TPX2 expression in malignant lymphoma (Heidebrecht
et al. 1997 ; Rudolph et al. 1998 , 1999 ), mantle cell lymphoma (Brizova et al. 2010 ;
Cordes et al. 2010 ), malignant nevocellular tumours (Heidebrecht et al. 1997 ),
salivary gland sarcoma (Shigeishi et al. 2009 ), laryngeal cancer (Cordes
et al. 2010 ), non-small cell lung cancer (Kadara et al. 2009 ), meningioma (Stuart
et al. 2011 ), cervical cancer (Chang et al. 2012 ) and breast cancer (Colak
et al. 2013 ). TPX2 is also a proliferation-associated protein that was found to be
overexpressed in BPDE-transformed human bronchial epithelial (16HBE-C) cells
(Zhang et al. 2008 ), is overexpressed in liver, lung, prostate and pancreatic cancers
(Wang et al. 2002 ), and has been identified as a candidate oncogene on 20q11.2
showing copy number-driven overexpression in non-small-cell lung cancer and
PDAC (Tonon et al. 2005 ). TPX2 targeting siRNAs consistently cause cell cycle
arrest and apoptosis in cancer cell lines (Warner et al. 2009 ). A siRNA library-
based screening revealed that TPX2 is one of the three genes that significantly
reduced the survival of multiple human tumour cell lines (Morgan-Lappe
et al. 2007 ). It is tempting to speculate that small molecule inhibitors or inhibitory
antibodies against TPX2 function as potent cytostatic agents directed specifically
against proliferating cells. In human HeLa cells, inhibiting the function of TPX2
leads to a very strong cell cycle arrest followed by apoptosis (Garrett et al. 2002 ;
Gruss et al. 2002 ), indicating that cancer cells essentially rely on the MT
polymerising activity of TPX2. Recently, withanone, a small molecule inhibitor
of cell proliferation from Withania somnifera , was suggested to target TPX2 in
intact cells and may thus give a perspective as a novel anti-cancer drug (Widodo
et al. 2010 ; Grover et al. 2012 ). Interestingly, modelling of a complex of Aurora A,
TPX2 and withanone predicts that the compound interferes with proper Aurora
A-TPX2 interaction (Widodo et al. 2010 ) and could thus selectively influence a
very defined event upon entry into mitosis. However, the exact molecular basis of
withanone's anti-proliferative potential in intact cancer cells remains to be deter-
mined and further characterisation of the compounds is required to validate the use
of TPX2 as a selective anti-cancer target.
7.6 Reading the RanGTP Gradient
The complex pattern of proteins and protein complexes released from importin and
localised via exportin, their dynamic interactions with MTs and other spindle
assembly proteins in space and time may help to envision how mitosis orchestrates
the complicated self-assembly program driving spindle formation upon induction
by RanGTP. Combinatorial interactions of more and more Ran-regulated factors
activated with time correlate with the exponential production of MT mass after
RanGTP addition to Xenopus cell-free extracts (Clausen and Ribbeck 2007 ; Petry
et al. 2013 ).