The Suppressor Function of TXNIP - Therapeutic Strategies in Cancer Biology and Pathology - page 131

TXNIP can block TGF-β/Smad mediated activation of EMT. TXNIP deficiency
leads to increased expression of TGF-β and of the TGF-β inducible transcription fac-
tors Snail and Slug. This has led to the degradation of E-cadherin and activation of
EMT, accompanied by a modest increase of Vimentin (Masaki et al., 2012).
TXNIP in Cell Proliferation and Apoptosis
The suppressive effects of TXNIP on cell proliferation and tumour growth are well
documented. These occur mainly by cell cycle arrest and by the activation of apop-
tosis signalling. The suppression of metastatic behaviour is obviously related to the
suppressive effects it exerts on cell motility and adhesion-dependent phenomena.
TXNIP engages many signalling systems to bring about these phenotypic outcomes
( Figure 24.1 ). Minn et al. (2005) transfected a pancreatic islet beta cell line to over-
express TXNIP and this resulted in the induction of apoptosis by the expression of
Bcl2 family genes; the ratio of pro-apoptotic Bax/anti-apoptotic Bcl2 increased several
fold together with increase of caspase-3. As shown in the figure, inhibition of the anti-
apoptotic Akt by TXNIP induces apoptosis and this might involve regulation of PTEN.
Embryonic fibroblasts derived from TXNIP knockout mice show an accumulation of
inactive (oxidised) PTEN and enhanced Akt activation together with increased growth
rates. TXNIP seems to be essential to maintain active PTEN, inhibit Akt phosphoryl-
ation and induce apoptosis (Hui et al., 2008). Wang et al. (2006) showed that dexa-
methasone induces TXNIP expression in a proper glucocorticoid-receptor mediated
manner and induced apoptosis in a murine T-cell lymphoma cell line and also normal
murine thymocytes. RAGE has been shown to induce the expression of TXNIP (Sbai
et al., 2010) but incongruously RAGE binds several ligands including S100β, S100A4,
S100A9, HMGB1, Amphoterin, amyloid fibrils, and others. The upregulation and acti-
vation of RAGE induces cell proliferation, invasion and metastasis.
TXNIP and Angiogenesis
Whether TXNIP influences angiogenesis, a process highly relevant in the metastatic
process, is still an open question, but indications are that it does influence angio-
genesis under given conditions. Kuljaca et al. (2009) showed that TXNIP inhibits
endothelial cell migration and angiogenesis. They have adequately unravelled the
molecular circuitry involving TXNIP in angiogenesis. They have demonstrated
that cyclin-dependent kinase inhibitor p21 waf1 promoted angiogenesis by suppress-
ing the transcription of TXNIP. Since TXNIP is a negative regulator of thioredoxin,
this results in an increase of secretion of thioredoxin, which is pro-angiogenic.
Conditioned media obtained from MCF-7 cells transfected with siRNA against p21
reduced endothelial cell migration and vascular sprouting. Knockdown of p21 led to
an increase in TXNIP and a resultant decrease in thioredoxin. In agreement with this
was their finding that siRNA specific for TXNIP promoted endothelial cell invasion.