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construct as a reporter for ER stress and downstream responses relevant
to the tumor microenvironment, a positive correlation between XBP1-
luciferase activity and tumor growth rates was observed for several primary
mammary tumor cells ( Spiotto et al., 2010 ). This branch is also implicated
in transcriptional regulation ofVEGF, an angiogenic factor highly expressed
in tumors ( Plate et al., 1992 ) that protects them against ischemic injury and
plays a prominent role in sustaining tumor growth ( Shweiki et al., 1992 ).
VEGF mRNA increases under conditions of ER stress, but when IRE1 is
silenced by shRNA, VEGF induction is decreased, resulting in the loss of
blood vessels. These authors also demonstrated that the two other branches
(PERK, ATF6) independently regulate VEGF expression and that inactiva-
tion of any one of these three pathways impairs VEGF upregulation as a
consequence of ER stress, suggesting that coordinated activation of all three
pathways is essential for increased VEGF expression ( Ghosh et al., 2010 ).
6.4.1.2. PERK Branch
Activation of the PERK branch is considered an essential part of the responses
triggered in tumor cells required for survival in hypoxia. In tumors, PERK
is activated, phosphorylates eIF2α and thereby favors activation of ATF4
and NRF2, transcription factors which promote cell survival by increas-
ing autophagy and activating antioxidant mechanisms. Initial evidence from
a study in MEF cells expressing an eIF2α mutant (S51A) that cannot be
phosphorylated by PERK indicated that survival of such cells under pro-
longed hypoxia was reduced ( Bi et al., 2005 ). PERK ablation decreased
tumor growth rates in nude mice and in PERK knockout mice, reduced
insulinoma formation and vascularization were observed ( Bi et al., 2005 ;
Gupta et al., 2009 ). The ATF4 pathway is also implicated in tumor adap-
tation in the response to hypoxia ( Ye et al., 2010 ). One of these tumor
adaptation responses is related to enhanced expression of VEGF, whereby
synthesis and processing in the ER for secretion ( Ferrara and Davis-Smyth,
1997 ) are increased in hypoxia by mechanisms involving the ATF4 pathway
( Roybal et al., 2004 ). On the other hand, secretion of de novo synthesized
VEGF is controlled by a heat-shock protein 70 family molecular chaper-
one localized in the ER (ORP150), which is upregulated under hypoxia
( Ozawa et al., 2001 ). In addition, PERK participates in the survival of
dormant tumor cells found in small, chemotherapy resistant and asymp-
tomatic tumors, via mechanisms involving augmented expression of BiP/
GRP78, reduced protein synthesis and exit from the cell cycle in the G1
phase ( Ranganathan et al., 2006 ). Alternatively, PERK facilitates survival
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