title: HS-173, a novel PI3K inhibitor suppresses EMT and metastasis in pancreatic cancer.
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.
authors: Department of Biomedical Sciences, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors: Marufa
authors: M
authors: Rumman
authors: Department of Biomedical Sciences, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors: Kyung Hee
authors: KH
authors: Jung
authors: Department of Biomedical Sciences, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors: Zhenghuan
authors: Z
authors: Fang
authors: Department of Biomedical Sciences, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors: Hong Hua
authors: HH
authors: Yan
authors: Department of Biomedical Sciences, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors: Mi Kwon
authors: MK
authors: Son
authors: Department of Biomedical Sciences, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors: Soo Jung
authors: SJ
authors: Kim
authors: Department of Biomedical Sciences, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors: Juyoung
authors: J
authors: Kim
authors: Department of Biomedical Sciences, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors: Jung Hee
authors: JH
authors: Park
authors: Department of Biomedical Sciences, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors: Joo Han
authors: JH
authors: Lim
authors: 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.
authors: Sungwoo
authors: S
authors: Hong
authors: Department of Biomedical Sciences, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors: Soon-Sun
authors: SS
authors: Hong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013449:Sulfonamides; C577242:ethyl 6-(5-(phenylsulfonamido)pyridin-3-yl)imidazo(1,2-a)pyridine-3-carboxylate
keywords: EMT; HS-173; PI3K; metastasis; pancreatic cancer