Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 259

inflammation-induced oncogenesis through heat-shock proteins ( Gold-
stein and Li, 2009 ). Both the ATF6 and IRE1 branches induce BiP/
GRP78 expression in conditions of ER stress and this chaperone promotes
ER homeostasis and resistance to apoptosis by interacting with BIK and
caspase-7 ( Rao et al., 2002 ; Reddy et al., 2003 ; Fu et al., 2007 ). Condi-
tional ablation of BiP/GRP78 in prostate abolishes tumorigenesis in a
PTEN-null mouse, where the chaperone is critical for neovasculariza-
tion during tumor growth and metastasis. Also, in a transgene-induced
breast cancer model, BiP/GRP78 was shown to favor tumor prolifera-
tion and angiogenesis ( Fu et al., 2008 ; Dong et al., 2011 ). The participa-
tion of BiP/GRP78 is also suggested from other studies. In particular,
a correlation between BiP/GRP78 expression and cancer progression is
observed in a number of other types of cancers, including gastric carcino-
mas, melanoma, hepatocellular carcinoma and breast cancer ( Shuda et al.,
2003 ; Lee et al., 2006 ; Daneshmand et al., 2007 ; Dong et al., 2008 ; Zheng
et al., 2008 ; Zhuang et al., 2009 ). Such elevated levels of BiP/GRP78 in
tumor cells suggest that basal UPR levels are increased and may contribute
to decreased apoptosis. Taken together, currently available data indicate
that enhancing the UPR and BiP/GRP78 expression favors adaptation
to the hypoxic environment and tumor growth under these restrictive
conditions. Moreover, essentially as a corollary, recent preclinical studies
have reported on the use of BiP/GRP78 inhibitors for cancer treatment
( Backer et al., 2009 ).
6.4.1.1. IRE1-XBP1 Branch
Several lines of evidence suggest that the IRE1-XBP1 branch of the UPR
is essential for tumor cell survival under hypoxic conditions and main-
tenance of malignancy ( Romero-Ramirez et al., 2004 ). For instance, in
XBP1-deficient cells, increased apoptosis and decreased clonogenic survival
are observed under hypoxic conditions. Upon subcutaneous injection of
immunodeficient mice with XBP1 knockout cells, decreased tumor growth
and higher sensitivity to hypoxia was observed in comparison to wild-type
controls ( Romero-Ramirez et al., 2004 ). Furthermore, downregulation of
XBP1 using specific shRNA diminished blood vessel formation in tumors
from mouse embryonic fibroblast and fibrosarcoma cells and expression of
the spliced form of XBP1 restored angiogenesis in cells expressing dominant
negative IRE1α ( Romero-Ramirez et al., 2009 ). The latter observations
provide evidence linking successful angiogenesis to the IRE1-XBP1 branch
in tumor cells. Moreover, in transgenic mice, expressing an XBP1-luciferase