The Role of b-Arrestins in Cancer - Progress in Molecular Biology and Translational Science - page 395

Smoothened (Smo) resulting in its activation and promotion of down-
stream Hh targets involved in cell division and the suppression of apopto-
sis. 79 Shh stimulation induces Smo to interact with ARRB2, resulting in
Smo internalization, while treatment with a Smo antagonist (cyclopamine)
prevents the interaction and internalization. 80 In pancreatic cancer-derived
cell lines and tissue samples, Shh expression was found significantly
increased. 79 Inhibition of Smo by cyclopamine treatment resulted in
decreased cell proliferation and increased apoptosis. 79 While the involve-
ment of ARRB proteins on Hh signaling has not been specifically shown
in a pancreatic model, it is likely that Smo internalization and activation is
ARRB dependent. Thus, future studies confirming the role of ARRB
proteins in Hh signaling may identify additional therapeutic targets for
pancreatic cancer treatment.
3.8. Glioblastoma
Few studies have been published specifically examining the role of ARRBs
in glioblastoma (GBM) formation and progression. One study performed
immunohistochemistry on GBM samples and identified a strong correlation
between grades II and III GBM and ARRB1 phosphorylation at Ser412,
such that GBMs expressed less phosphorylated ARRB1 than non-neoplastic
brain. 81 Survival curves found that GBM patients negative for phosphory-
lated ARRB1 at Ser412 had significantly decreased survival. 81 The total
and phosphorylated expression of ARRB2 was not examined in GBM
samples and would be worth investigating in the future to determine if there
is any differential expression between the two proteins, similar to that
found in breast cancer. 82 GBM, as well as medulloblastoma, has been found
to overexpress CXCR4 and its ligand CXCL12, and as mentioned before,
increased tumor cell migration by CXCR4 signaling is mediated through
ARRB proteins. 37,83 While CXCR4 antagonists (AMD3100 and
TC14012) initially reduce the growth of primary brain tumors, the
same antagonists activate CXCR7 signaling mediated through ARRB. 83,84
In astrocytes, CXCR7 activation of ERK and Akt by CXCL12
was abolished by pertussis toxin and thus is mediated through G i/o
proteins. 85 But in astrocytes stimulated with the CXCR7 ligand, I-TAC/
CXCL11, ERK and Akt activation was ARRB dependent and not pertussis
toxin sensitive. 85 More studies need to be done on the effects of ARRB
pathway activation to improve current therapies that target CXCR4 and
CXCR7 signaling.