The Suppressor Function of TXNIP - Therapeutic Strategies in Cancer Biology and Pathology - page 130

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The Suppressor Function of
TXNIP

TXNIP (also known as vitamin D3 upregulated protein 1) is an arrestin family pro-
tein (Alvarez, 2008). Arrestins are important signalling regulators. GPCRs, arrestins
and G-receptor kinases (GRKs) are activated leading to the activation or inhibition
of many signalling systems. β-Arrestin for instance is involved with ERK/p38/JNK,
Akt and NF-κB pathways, and via GRKs MEK1 (MKK1), RKIP/Raf1 and PI3K/Akt
pathways are activated (Lefkowitz et al., 2006; Reiter and Lefkowitz, 2006). TXNIP
is localised in the nucleus. It is a negative regulator of thioredoxin (Nishiyama
et al., 1999; Nishinaka et al., 2004). With possible involvement in a wide range of
signalling systems, it is small wonder that TXNIP subserves several cellular func-
tions, for example in cell proliferation (Han et al., 2003; Kuljaca et al., 2009), cell
apoptosis (Chen et al., 2008b), immune response (Lee et al., 2005; Son et al., 2008),
among others and significantly interferes with the function of some suppressor genes
( Figure 24.1 ).
There is much more definable success with establishment of the suppressor func-
tion of TXNIP which was recognised to be important in the activation of KiSS1
metastasis suppressor by CRSP3. Goldberg et al. (2003) noticed that CRSP3 upregu-
lated both KiSS1 and TXNIP in their quest to elucidate the upstream and downstream
signalling cascade of KiSS1. In breast cancer, TXNIP and TXNRD1 (thioredoxin
reductase 1) are both closely related to metastasis-free survival of node negative
breast cancer patients. TXNIP expression indicated favourable prognosis (Cadenas
et al., 2010). Not only this, these authors found that HER2 (ErbB2) + tumours
expressed higher levels of TXNRD1. When HER2 expression was induced in
MCF-7 cells, a rapid increase in TXNRD1 and a robust decrease in TXNIP occurred.
Possibly, there is a practical benefit here.

TXNIP

E-cadherin CRSP3 KiSS1

HER2 TGF-β

miRNAs

ERK/p38/
JNK Akt NF- κ B

EMT Cell proliferation Apoptosis EMT

Figure 24.1 The signalling systems deployed in the suppressor effects of TXNIP. The Wnt/
β-catenin pathway may be activated by miRNA-373 is not shown here.