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is due to PrP that prevents necrosis, autophagy, or apoptosis induced by ischemia.
The underlying mechanism for PrP protection of neural cell survival under Bax
challenge was first identified by Bounhar et al. [ 66 ]. Working with human primary
neuron and breast carcinoma MCF-7, Bounhar et al. showed that PrP potently inhib-
its Bax-induced cell death, and the protection role requires the octapeptide repeat
regions but not the GPI anchor, thus implying that lipid raft location of PrP is not
necessary for this anti-apoptotic role of PrP. To further investigate if the protection
by PrP against Bax-induced cell death requires other Bcl-2 family members,
Bounhar et al. [ 67 ] challenged Saccharomyces cerevisiae lacking Bcl-2 genes with
exogenous expression of Bax and found that PrP overcomes Bax-mediated S phase
growth and cell death. This result suggests that PrP does not require other Bcl-2
family proteins to protect against Bax-mediated mitochondrion-dependent apopto-
sis. In addition to protect breast carcinoma MCF-7 cells from Bax-induced cell
death, PrP also prevents breast cancer cell death induced by Adriamycin (ADR) and
TRAIL. In contrast to Bcl-2-independent protection of S. cerevisiae, downregula-
tion of PrP is accompanied with reduced Bcl-2 expression, thus suggesting Bcl-2 is
the target downstream of PrP to prevent cancer cell death [ 24 ]. Drug resistance by
PrP was also observed in gastric cancer cell line and colon cancer cells [ 25 , 68 ], and
such drug resistance in gastric cancer is mediated by the first four octapeptide
repeats, but not the fifth octapeptide repeat at the N-terminus of PrP [ 69 ]. Although
suffered a limited sample size, probably the most intriguing observation is a retro-
spective analysis of breast cancer patients that showed patients with estrogen
receptor- negative and PrP-positive staining are resistant but patients with estrogen
receptor negative and PrP negative are sensitive to adjuvant chemotherapy [ 70 ].
This result not only points out that cancer cells expressing PrP are drug resistant but
also identifies PrP as a potential biomarker for molecular typing of cancer cells.
13.4 PrP Plays a Role in Inflammation Response
It is widely accepted that chronic inflammation may result in cancer. Due to its high
expression in lymphatic tissues, PrP have long been implicated in immune response
[ 71 ]. It was later shown that T-cell activation may be modulated by PrP expression
[ 72 ]. However, the role of PrP in inflammation was not well established. In normal
skin, there is little expression of PrP mainly confined to keratinocytes. But expres-
sion of PrP was strongly upregulated in both keratinocytes and infiltrating mono-
nuclear cells in psoriasis and contact dermatitis, two inflammatory skin diseases.
Strong expression of PrP can also be detected in viral warts. Cytokines such as
transforming growth factor alpha (TGFα) or interferon-γ resulted in an increase of
PrP in primary cultured keratinocytes [ 73 ]. Similarly, in patients infected with
Helicobacter pylori, higher expression of PrP at mRNA and protein levels was
detected, which was correlated with gastric inflammation. More importantly, when
H. pylori are eradicated, expression of PrP is no longer detectable [ 74 ]. In peripheral
immune system, lack of PrP expression affects peripheral inflammation induced by
X. Yang et al.