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

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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-beta-induced migration and invasion, as well as reversed TGF-beta-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.
Publisher
IMPACT JOURNALS LLC
Issue Date
2016-11
Language
English
Article Type
Article
Keywords

EPITHELIAL-MESENCHYMAL TRANSITION; SQUAMOUS-CELL CARCINOMA; E-CADHERIN EXPRESSION; TGF-BETA; BREAST-CANCER; ANTICANCER ACTIVITY; DRUG-RESISTANCE; TUMOR-GROWTH; MIGRATION; PATHWAY

Citation

ONCOTARGET, v.7, no.47, pp.78029 - 78047

ISSN
1949-2553
DOI
10.18632/oncotarget.12871
URI
http://hdl.handle.net/10203/219636
Appears in Collection
CH-Journal Papers(저널논문)
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