Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 265

6.4.5.1. IRE1-XBP1 Branch
The IRE1-XBP1 branch has been suggested to connect to apoptosis by
recruiting TRAF2, activating procaspase-4, and subsequently caspase-9 and
caspase-3, thereby triggering mitochondria-independent apoptosis ( Wu and
Kaufman, 2006 ). Paraquat ( N , N ′-dimethyl-4,4′-bipyridinium dichloride), a
widely used herbicide, induces UPR, activating the IRE1/ASK1/JNK axis,
leading to apoptosis in neuroblastoma SH-SY5Y cells ( Yang et al., 2009 ).
6.4.5.2. PERK Branch
The PERK branch can be activated during loss of adhesion and regulate cel-
lular fate. Inhibition of PERK signaling by the expression of two dominant
negative PERK mutants results in hyperproliferative MCF10A mammary
epithelial cells. In the same study, introduction of mutated PERK converted
MCF10A cells into tumorigenic cells after implantation in denuded mouse
mammary fat pads ( Sequeira et al., 2007 ). Moreover, the PERK branch
also regulates angiogenesis in response to hypoxia. Using microarray analy-
sis in K-ras transformed PERK −/− cells, Blais et al. (2006) demonstrated
that under hypoxic conditions, several proangiogenesis transcripts are less
efficiently translated, resulting in increased apoptosis, nonfunctional, irregu-
larly structures blood vessels and reduced microvessel density. The induction
of UPR can sensitize tumor cells to cisplatin-induced death. Cisplatin is
widely used to treat solid tumors and it is believed to kill cells by binding
to DNA and interfering with repair, thereby activating cell cycle arrest and
apoptosis ( Pascoe and Roberts, 1974 ). However, cisplatin also efficiently
induces UPR and activates caspase-12 in a nucleus-independent manner in
human melanoma and colon cancer (HCY116) cytoplasts. In summary, the
proapoptotic effects of cisplatin not related to its ability to bind to DNA
but may also be linked to effects on protein folding ( Mandic et al., 2003 ). Addi-
tionally, a correlation between UPR and sensitization to DNA-crosslinking
agents, such as carboplatin ( Yamada et al., 1999 ), melphalan and BCNU
( Chatterjee et al., 1997 ), has been observed. The mechanisms underlying
these observations are not clear but it is tempting to speculate that the
protein complexes required for DNA repair might be adversely affected by
changes in protein synthesis and degradation when UPR is triggered.
6.4.5.3. ATF6 Branch
During metastasis, tumor cells must detach from the ECM, which fre-
quently leads to anoikis. CHOP, a downstream effector in both the ATF6
and PERK branches, is widely attributed proapoptotic functions ( Zinszner