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calcium concentration ( Berridge, 2002 ). Calcium seems to be mobilized
between the ER and mitochondria in a process called the “ER-mitochon-
dria calcium cycle” (ERMCC), which is driven by the synaptic excitatory
input and electrical activity in neurons rather than occurring spontaneously
as in nonexcitable cells. Given the hypothetical nature of this model, it can
be speculated that reducing ER calcium release may restore balance to the
ERMCC, concomitant with a reduction in ER protein throughput and
increasing protein-folding fidelity. A different strategy could be to block the
mitochondrial uniporter and thereby prevent mitochondrial calcium over-
load but the effect of this on overall cellular metabolism needs to be revisited.
As we can see from the previous examples, prolonged ER stress and
mitochondrial dysfunction is a key feature of a broad range of neurodegen-
erative diseases, suggesting that disruption of the ER-mitochondrial axis
may be responsible for the metabolic alterations detected and associated
with these diseases. Future studies should focus in the establishment of a
clear relationship between the metabolic regulation exerted by the ER on
mitochondria and how this connection might be related to other features
of these diseases.
6.4. UPR and Cancer
Elevated proliferation rates of cancer cells observed during tumor devel-
opment require increased membrane and protein synthesis. These changes
pose major challenges to the molecular machinery within and associated
with the ER. In this context, steps of adaptation involving an increase in
the ability to sustain adequate protein folding are essential. Cell proliferation
associated with tumor growth often takes place in hypoxia and conditions
of limited substrate availability (“starvation”). As one possibility, tumor cells
adapt to this “stressful” environment by activating the UPR and, in this sce-
nario, an adaptive UPR response favors tumor growth. Alternatively, how-
ever, a sizable body of literature is also available indicating that enhancing
the UPR may represent a mechanism to preclude tumor progression. Both
these facets must be taken into account in developing a better understand-
ing of how the UPR participates in oncogenesis and particularly how such
insights might be exploited in novel cancer therapies. In this section, we will
focus the discussion on such aspects.
6.4.1. UPR in Tumor Cell Survival
The ability to upregulate the UPR appears to be essential for tumor
survival ( Bi et al., 2005 ). Indeed, the UPR has been implicated in
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