Apurinic/apyrimidinic
endonuclease 1/redox factor-1 (Ape1/Ref-1, Ape1) is a multifunctional
protein that is upregulated in human
pancreatic cancer. Ape1 redox domain plays an essential role in regulating the effects of
reactive oxygen species (ROS) generated during physiological metabolism and pathological stress. In the present study, we explored whether Ape1 and ROS affect WNT/β-
catenin signaling. We used
E3330, a small molecule inhibitor of the redox activity of Ape1, and a
siRNA approach to knock down Ape1, in two human
pancreatic cancer cell lines. Inhibition of Ape1 resulted in growth suppression of
pancreatic cancer cells, increased ROS levels, upregulation of β-
catenin and c-myc and downregulation of
cyclin D1. Consistent with these data, overexpression of Ape1 in
pancreatic cancer cells reduced ROS and c-myc levels and increased
cyclin D1 levels. Moreover, treatment of
pancreatic cancer cells with H2O2 to induce oxidative stress resulted in upregulated ROS levels, decreased Ape1 at both the
mRNA and
protein level, and alterations in WNT/β-
catenin pathway components. Finally, treatment of
pancreatic cancer cells with the WNT/β-
catenin inhibitor IWR-1 resulted in growth inhibition, which was greatly enhanced when combined with
E3330 treatment. In summary, our results demonstrate that ROS is an important intracellular messenger that can modulate WNT/β‑catenin signaling. The present study provides interesting new insight into crosstalk between the redox function of Ape1 and WNT/β-
catenin signaling in
cancer cells. Furthermore, our data show that the combination of Ape1 and WNT inhibitors enhanced the inhibition of pancreatic cell proliferation. These results provide a promising novel therapeutic strategy for treating
pancreatic cancer in future.