Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 261

of extracellular matrix (ECM)-detached cells by promoting autophagy, ATP
production and an antioxidant response in human mammary epithelial cells.
This mechanism may potentially be exploited by ECM-detached tumor
cells in breast ductal carcinoma in situ lesions ( Avivar-Valderas et al., 2011 ).
However, paradoxically, PERK ablation was recently also shown to promote
mammary tumorigenesis in aged mice through increased ROS and DNA
damage. In doing so, PERK ablation favors DNA mutation and neoplastic
growth ( Bobrovnikova-Marjon et al., 2010 ).
6.4.1.3. ATF6 Branch
The role of the ATF6 branch in cancer has been poorly explored to date,
although indirect evidence exists indicating that ATF6α is an important
modulator of chronic ER stress. For instance, a complex between XBP1
and ATF6α that upregulates ERAD components is detected in MEF cells
( Yamamoto et al., 2007 ). This process must be carefully regulated as cells
degrade proteins whose synthesis consumes high levels of ATP. Moreover,
the ERAD pathway per se also requires large amounts of ATP. A second
piece of evidence implicating ATF6α as a key regulator in persistent ER
stress was obtained using cells from ATF6α knockout mice. There, reduced
survival following long-term ER stress correlated with lower levels of
chaperones, such as BiP and GRP94 ( Wu et al., 2007 ). Indirect evidence
implicating ATF6 is provided by studies identifying p50ATF6 within the
nucleus in moderately or poorly differentiated hepatocellular carcinomas
( Shuda et al., 2003 ). On the other hand, ATF6 activation is crucial to long-
term survival of tumors by augmenting resistance to chemotherapy, nutrient
starvation and stress in quiescent squamous carcinoma cells, where ATF6
increases Rheb expression, which in turn activates mTOR activity in an
Akt-independent manner ( Schewe and Aguirre-Ghiso, 2008 ). Finally, acti-
vation of the UPR, through PERK, IRE1α and ATF6, promotes VEGF
expression and subsequent initiation of the angiogenic program ( Ghosh
et al., 2010 ).
6.4.2. UPR as an Adaptive State in Cancer
Generally, normal, nonsecretory cells are not subject to permanent ER stress
and the UPR pathways exist in a quiescent state. In contrast, tumor cells
must adapt to hypoxia and a stressful environment, and do so in ways, which
require developing an adaptive UPR state. Although the precise molecular
signals that induce this state in tumor cells remain poorly defined, high
ROS levels and protein synthesis rates, which are prevalent in cancer cells,