Oncotarget

Research Papers:

HS-173, a novel PI3K inhibitor suppresses EMT and metastasis in pancreatic cancer

Marufa Rumman, Kyung Hee Jung, Zhenghuan Fang, Hong Hua Yan, Mi Kwon Son, Soo Jung Kim, Juyoung Kim, Jung Hee Park, Joo Han Lim, Sungwoo Hong and Soon-Sun Hong _

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Oncotarget. 2016; 7:78029-78047. https://doi.org/10.18632/oncotarget.12871

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Abstract

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

Correspondence to:

Soon-Sun Hong, email: hongs@inha.ac.kr

Keywords: pancreatic cancer, metastasis, EMT, PI3K, HS-173

Received: August 02, 2016     Accepted: October 12, 2016     Published: October 25, 2016

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.


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