Abstract
Pancreatic cancer is one of the most aggressive solid malignancies prone to metastasis. Epithelial-mesenchymal transition (EMT) contributes to cancer invasiveness and drug resistance. In this study, we investigated whether HS-173, a novel PI3K inhibitor blocked the process of EMT in pancreatic cancer. HS-173 inhibited the growth of pancreatic cancer cells in a dose- and time-dependent manner. Moreover, it significantly suppressed the TGF-β-induced migration and invasion, as well as reversed TGF-β-induced mesenchymal cell morphology. Also, HS-173 reduced EMT by increasing epithelial markers and decreasing the mesenchymal markers by blocking the PI3K/AKT/mTOR and Smad2/3 signaling pathways in pancreatic cancer cells. In addition, HS-173 clearly suppressed tumor growth without drug toxicity in both xenograft and orthotopic mouse models. Furthermore, to explore the anti-metastatic effect of HS-173, we established pancreatic cancer metastatic mouse models and found that it significantly inhibited metastatic dissemination of the primary tumor to liver and lung. Taken together, our findings demonstrate that HS-173 can efficiently suppress EMT and metastasis by inhibiting PI3K/AKT/mTOR and Smad2/3 signaling pathways, suggesting it can be a potential candidate for the treatment of advanced stage pancreatic cancer.
Highlights
Pancreatic cancer is one of the most aggressive solid malignancies with an extremely poor prognosis of an overall 5-year survival rate of
Our findings demonstrate that HS-173 can efficiently suppress Epithelial-mesenchymal transition (EMT) and metastasis by inhibiting PI3K/AKT/mTOR and Smad2/3 signaling pathways, suggesting it can be a potential candidate for the treatment of advanced stage pancreatic cancer
Our study revealed that HS-173 could efficiently suppress Transforming growth factor-β (TGF-β)-induced migration, invasion, and metastasis by inhibiting EMT process through the regulation of PI3K/AKT/mTOR and Smad2/3 signaling pathways, suggesting that HS-173 is a potential candidate for advanced stage treatment of pancreatic cancer with metastasis
Summary
Pancreatic cancer is one of the most aggressive solid malignancies with an extremely poor prognosis of an overall 5-year survival rate of
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