Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 262

are likely to be involved. In normal mammalian cells, considerable evidence
is available indicating that excessive ER stress induces the apoptotic pro-
gram through CHOP and JNK activation ( Zinszner et al., 1998 ; Hatai et al.,
2000 ). Additionally, mitochondrial calcium overload promotes apoptosis
mediated by ERO1α and BIM expression ( Tabas and Ron, 2011 ). How-
ever, unlike normal cells, tumor cells often become resistant to apoptosis
either by increasing the expression of antiapoptotic proteins or by reducing
the function of proapoptotic factors. In an analogous manner, tumor cells
also modulate their UPR so as to favor proliferation, antioxidant responses,
metabolic plasticity and survival in conditions of hypoxia and nutrient star-
vation. Taken together, these data suggest that during tumor development,
cancer cells undergo an adaptive response that facilitates their survival by
downregulating components of the UPR response that are utilized to pro-
voke death in normal cells.
6.4.3. ER-Mitochondria Connection
In addition to these ER-localized stimuli, mitochondrial stress induced by
calcium, nitric oxide or oligomycin is also known to activate PERK ( Lu
et al., 2009 ; Silva et al., 2009 ; Bollo et al., 2010 ). Additionally, nitric oxide
induces mitochondrial calcium release and activation of calcium-dependent
serine protease, which cleaves p90ATF6 to yield p50ATF6. The later trans-
locates to the nucleus and promotes transcription of cytoprotective GRP78
( Xu et al., 2004 ). Thus, both mitochondrial and ER stress can induce UPR
activation. Moreover, it is important to bear in mind that calcium shut-
tling between ER and mitochondria plays an important role in regulating
metabolism, autophagy and apoptosis. Available evidence indicates that as
an early response to ER stress, ER-mitochondria coupling, mitochondrial
OXPHOS activation and enhanced ATP synthesis are observed ( Bravo
et al., 2011a, 2011b ). Several studies now show that MAMs are involved
in the transfer of calcium from ER to mitochondria and proteins specifi-
cally localized in this compartment regulate this function. Moreover, loss-
of-function mutations of some proteins localized in MAMs promote cell
proliferation and desensitize cells to apoptotic stimuli ( Chen et al., 2004 ;
Simmen et al., 2005 ; Hayashi and Su, 2007 ). Based on such observations,
it has been proposed that in tumor cells, the interaction between ER and
mitochondria may be affected in a manner that alters the UPR response.
PACS-2 is a protein involved in protein sorting that localizes to MAMs
( Simmen et al., 2005 ). Reduction or depletion of PACS-2 expression has
been reported in cancer tissues ( Aslan et al., 2009 ). PACS-2 knockdown