Biology Reference
In-Depth Information
on this, one may hypothesize that alterations in the ER-mitochondria cou-
pling are important for adaptive ER responses to stress in cells exposed to
hypoxia or starvation, such as those found in tumor cells.
6.4.4. Therapeutic Strategies Based on Suppressing the UPR
Most of the time, ER stress responses are not observed in normal cells, but in
tumor cells, the opposite seems to be the case. This difference between nor-
mal and tumor cells can be exploited to develop drugs that target the UPR
as anticancer agents. In this respect, two approaches have been described:
namely either stimulation of accumulation of misfolded proteins in the ER
to overcome UPR, or inhibition of adaptive and antiapoptotic pathways
( Li et al., 2011 ). An example within the first group is bortezomib, a protea-
some inhibitor that has efficacy in multiple myeloma ( Obeng et al., 2006 ),
as well as cytotoxic effects in breast, colorectal, ovarian, pancreatic, lung
and oral cancer cells ( Sterz et al., 2008 ). Other chemical agents that cause
accumulation of misfolded proteins are the ERAD inhibitors. For instance,
Eeyarestatin I, an inhibitor of the ER-associated p97 ATPase required for
ERAD ( X. Wang et al., 2008 ), has been shown to be cytotoxic for hepato-
cellular carcinoma (HepG2) cells ( Cross et al., 2009 ). Given the importance
of chaperones in the UPR, the use of agents that target ER chaperones as
anticancer drugs, emerges as an interesting possibility. Indeed, the HSP90
inhibitor 17AAG (17-allyamino-17-demethoxygeldanamycin) and radici-
col activate all three branches of UPR in human myeloma cells, inhibiting
proliferation and increasing the expression of BiP and GRP94 chaperones,
thereby promoting caspase-dependent cell death ( Davenport et al., 2007 ).
For versipelostatin, a BiP/GRP78 inhibitor, cytotoxicity toward glucose-
deprived tumor cells was observed, as well as inhibition of UPR in cell lines
derived from solid tumors, including human colon cancer HT29, fibrosar-
coma HT1080, and stomach cancer MKN47 cells ( Park et al., 2004 ). Also,
inhibiting the adaptive IRE1α/XBP1 pathway has been shown to result in
antitumor activity. For example, irestatin an inhibitor of XBP1s transcrip-
tional activity reduces growth and survival of hypoxia-exposed myeloma
cells in vitro and in subcutaneous xenografts ( Li et al., 2011 ).
6.4.5. UPR in Tumor Cell Death
Thus far, we have reviewed aspects of the UPR that favor the survival of
tumor cells. However, persistent or excessive ER stress is known to trig-
ger cell death, mainly apoptosis, by both mitochondria-dependent and
-independent pathways ( Rao et al., 2002 ; Breckenridge et al., 2003 ).
Search WWH ::




Custom Search