Anti-tumor Activity of the Small Molecule Inhibitor PRI-724 Against β-Catenin-activated Hepatocellular Carcinoma
Ryosuke Gabata, Kenichi Harada, Yuki Mizutani, Hirofumi Ouchi, Kaori Yoshimura, Yasunori Sato, Azusa Kitao, Kiminori Kimura, Hiroyuki Kouji, Tomoharu Miyashita, Hidehiro Tajima, Tetsuo Ohta
Abstract
Background/Aim: CBP is a transcriptional coactivator in the Wnt/β-catenin pathway that is related to cell kinetics and differentiation. This study aimed to characterize β-catenin-activated hepatocellular carcinoma (HCC) and evaluate the direct effects of PRI-724 (a selective inhibitor of Wnt/β-catenin/CBP signaling) on HCC. Materials and Methods: Immunohistochemistry for β-catenin was performed in 199 HCC resected samples. Moreover, using cultured HCC cell lines, cell kinetics and its related proteins were analyzed after treatment of cells with C-82 (active form of PRI-724). Results: Nuclear β-catenin expression was found in 18% of HCC cases and the tumor sizes in these positive samples were larger. In HCC cell lines with a constitutively activated β-catenin, C-82 inhibited cell proliferation. C-82 led to an increase in the percentage of cells in the G<sub>0</sub>/G<sub>1</sub> phase of the cell cycle. The percentage of cells in the sub-G<sub>1</sub> phase also increased. Moreover, C-82 treatment significantly decreased the expression of cell proliferating markers and increased the expression of apoptosis-related proteins. Conclusion: PRI-724(C-82) may be a novel drug for β-catenin-activated HCC therapy.