HS-173, a novel PI3K inhibitor suppresses EMT and metastasis in pancreatic cancer
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Marufa Rumman1,*, Kyung Hee Jung1,*, Zhenghuan Fang1, Hong Hua Yan1, Mi Kwon Son1, Soo Jung Kim1, Juyoung Kim1, Jung Hee Park1, Joo Han Lim1, Sungwoo Hong2, Soon-Sun Hong1
1Department of Biomedical Sciences, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea
2Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), and Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS), Daejeon 34141, South Korea
*These authors have contributed equally to this work
Soon-Sun Hong, email: firstname.lastname@example.org
Keywords: pancreatic cancer, metastasis, EMT, PI3K, HS-173
Received: August 02, 2016 Accepted: October 12, 2016 Published: October 25, 2016
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.
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