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A Novel Compound Inhibits Pancreatic Cancer Cell Invasion, Tumor Sphere Formation, and In Vivo Tumor Growth in Mice by Suppressing EMT
Author(s) -
Wang Tao,
Dong Ruochen,
Chen Ping,
Baltezor Michael,
Weir Scott,
Chen Qi
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.670.6
Subject(s) - pancreatic cancer , cancer research , epithelial–mesenchymal transition , gentamicin protection assay , cell migration , metastasis , cancer stem cell , cancer cell , mtt assay , cancer , cell growth , chemistry , viability assay , cell culture , cell , in vivo , biology , medicine , biochemistry , genetics , microbiology and biotechnology
Objective Epithelial to Mesenchymal Transition (EMT) has been proposed to contribute importantly to metastasis, cancer stem cell (CSC) generation and drug resistance in many cancers. Targeting EMT may be promising to benefit cancer treatment. Our previous high throughput screening study has identified a potential EMT inhibitor (namely, C150) in pancreatic cancer cells. Here, we sought to investigate the activities of C150 in inhibiting pancreatic cancer cell invasion, CSCs and tumor growth in mice, and its mechanisms of EMT inhibition. Methods Cell viability was detected by MTT assay. Cell migration/invasion was detected by Boyden chamber trans‐well migration‐invasion assay, wound scratch assay and a 3‐dimension (3D) cell invasion assay. Tumor sphere formation in stem cell medium was used to indicate CSC inhibition. In vivo tumor growth was evaluated in an orthotopic mouse model of pancreatic cancer. EMT marker proteins were examined by western blot. Results C150 exhibited a well‐separated cytotoxicity between pancreatic cancer cells and non‐cancerous cells, with IC 50 values of 1~2.5 μM in multiple pancreatic cancer cell lines and >25 μM in a non‐cancerous pancreatic epithelial cell line (hTERT‐HPNE). C150 was found to significantly inhibit PANC‐1 cell invasion in the 3‐dimension (3D) cell invasion model, the wound scratching assay and the Boyden Chamber trans‐well migration‐invasion assay. Pancreatic tumor sphere formation was strongly inhibited by C150 at concentrations as low as 0.4 μM in PANC‐1 cells and 0.05 μM in MiaPaCa‐2 cells, indicating preferable inhibition of pancreatic cancer stem cells. In the orthotopic pancreatic cancer mouse model, C150 significantly reduced tumor growth at the dose of 15 mg/kg, 3x weekly IP injection. C150 decreased the mesenchymal marker N‐cadherin while increased epithelial markers of ZO‐1 and Claudin‐1. Further studies revealed that C150 significantly reduced total and nuclear levels of Snail and β‐Catenin, two important transcription factors that contribute to EMT and cancer stem cells in pancreatic cancer. Conclusion The novel compound C150 inhibited pancreatic cancer cell migration, invasion, tumor sphere formation and in vivo tumor growth in mice, by inhibiting EMT through Snail and β‐Catenin down‐regulation. The study of detailed mechanisms on how C150 reduced Snail and β‐Catenin protein levels is currently ongoing. Support or Funding Information Institutional Development Award (IDeA) of NIH and State of Kansas Grant # 8P30GM103495, KU Cancer Center Lied Basic Science grant 2018 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .