D. ROBBINS ET AL. 23
and activity when compared with promotion-sensitive P+
cells. In addition, several studies have shown that MnSOD
may act as a novel tumor suppressor gene and that over-
expression of MnSOD can significantly decrease tumor
promotion and key oncogenic survival and pro-inflam-
matory signaling pathways such as activator protein 1
(AP-1) and NF-
B [19-21]. Therefore, regulating the int-
racellular redox status has the potential to augment the
effects of current chemotherapeutic treatments and also
block survival and pro-inflammatory pathways in tumor
promotion sensitive cancer cells.
On the contrary, several studies have suggested that
knockdown of APE1/Ref-1 can lead to apoptosis. APE1
/Ref-1 is known to be induced by oxidative stress [22].
However, APE1/Ref-1 expression has been shown to be
inversely correlated with apoptosis, suggesting an anti-
apoptotic function of the multifunctional protein [23].
Unnikrishnan and colleagues presented data that oxida-
tive stress can alter the function of APE1/Ref-1 and the
apoptotic response was increased in APE/Ref-1 haploin-
sufficient mice [24]. Within this study heterozygous de-
letion of APE1/Ref-1 resulted in decreased NF-
B DNA
binding activity, accompanied by increases in GADD45
gene expression, p53 stability and caspase activity [24].
Previous studies have also shown that loss of APE1
/Ref-1 resulted in increased TNF-induced apoptosis [25].
In addition, homozygous deletion of the APE1/Ref-1
gene is embryonic lethal, suggesting the importance of
APE1/Ref-1 expression in cell survival. Therefore, mo-
dulating APE1/Ref-1 expression can play either a cell
survival or apoptotic role in tumorigenesis, but yet iden-
tifies APE/Ref-1 as a key controller of intracellular redox
changes in chemoprevention. Clinically, APE1/Ref-1 va-
riants have been identified in the human population [26];
and these variants have been associated with increased
cancer risk. Together, these data point toward an ap-
proach to improve drug target specificity and personal-
ized medicine in the prevention and treatment of tumors
with upregulated APE1/Ref-1 expression. Nevertheless,
further studies are ongoing to determine whether the sig-
nificant decrease seen in the colony-forming ability of
JB6 P+ cells was due to apoptosis or changes in mito-
chondrial function. So far, we have not found any associ-
ated toxicity following siRNA transfection and no indi-
cations of an apoptotic phenotype in cells that underwent
transfection. Moreover, we will continue to assess the
role of APE1/Ref-1 redox activity in early tumor promo-
ntion by utilizing known antioxidant-inducing natural
products to determine whether antioxidant expression
can modulate the redox functions of APE1/Ref-1 in early
stage skin carcinogenesis. In conclusion, our results sug-
gest that Ref-1 promotes early tumorigenesisby via con-
tributing to NF-κB activation and the pro-inflammatory
response. Therefore, Ref-1 might be able to serve as a
novel target for chemoprevention.
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