Therapeutic Targeting of TGF-B Signalling - Therapeutic Strategies in Cancer Biology and Pathology - page 50

pancreatic cancer cells that are resistant to the drug. SB525334 significantly increased
apoptosis of cell death in the resistant cells and this appears to be due to the inacti-
vation of Akt signalling (Kim et al., 2012b). Finally, the ubiquitous miRNAs should
not go unheeded from this scenario. According to Mizuno et al. (2009), miRNA-210
inhibits the TGF-β R1b receptor.
Inhibition of Type RIII Function
Among the regulatory components of the canonical Smad signalling system are
betaglycan (herein referred to as RIII) and endoglin (CD105), which share some
sequence homology and which are often described as accessory type III receptors
of the TGF-β family. RIII mediates both canonical and non-canonical signalling by
TGF-β family members and also participate in ligand independent signalling.
The co-receptor RIII is widely regarded as a tumour suppressor. It has been
implicated in the regulation of cell proliferation, and angiogenesis and its loss is
believed to promote tumour progression. RIII expression is reduced or lost in many
neoplasms. Restoration of its expression in multiple myeloma cells inhibits cell pro-
liferation and motility (Lambert et al., 2011). A similar situation has been reported
in prostate cancer where loss of expression of RIII has been linked with LOH of
the RIII encoding gene. With LOH found only in around 58% of specimens, loss of
expression seems to be compounded by changes in epigenetic regulation. Although
RIII expression reduced cell invasion, but it had no effect on cell proliferation.
Underscoring an obvious link with invasive capacity, the loss of RIII correlated with
the expression of PSA (Prostate-specific antigen) in prostate cancer suggesting a
potential relationship with progression (Turley et al., 2007). LOH at the RIII locus
has also been reported in breast cancer, where loss of RIII expression correlated with
disease progression and poorer prognosis (Dong et al., 2007a).
Compatible with these findings, loss of RIII, but not of RI and RII, appears to
be conducive to EMT. The activation of EMT accompanying the loss of RIII possi-
bly occurs without the mediation of E-cadherin or its regulator transcription factors.
Although this occurs subsequent to the loss of RIII, maintaining RIII levels suppresses
EMT without affecting the expression levels of E-cadherin. Also suppression of RIII
with shRNA promotes EMT without affecting the expression of E-cadherin or Snail
(Gordon et al., 2008). It seems possible that signalling might operate via other path-
ways and independently of both canonical and non-canonical systems. MicroRNAs are
known to activate EMT independently of both. Also TGF-β can promote EMT by the
mediation of microRNAs. Another example of RIII functioning independently of both
canonical and non-canonical pathways is the induction of apoptosis by experimentally
upregulation of RIII in vitro and in vivo murine models of clear cell renal carcinoma.
Here apoptosis was induced by p38 MAPK signalling (Margulis et al., 2008). Once
again one can invoke the intervention by microRNAs. For instance, miRNA-137 can
target cdc42 and inactivate it and lead cells into G1 arrest and into the apoptosis path.