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Oncotarget. 2016 Nov 22;7(47):78029-78047. doi: 10.18632/oncotarget.12871.

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

Author information

1
Department of Biomedical Sciences, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
2
Department 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.

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.

KEYWORDS:

EMT; HS-173; PI3K; metastasis; pancreatic cancer

PMID:
27793006
PMCID:
PMC5363641
DOI:
10.18632/oncotarget.12871
[Indexed for MEDLINE]
Free PMC Article

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