Inhibition of Migration, Invasion and Drug Resistance of Pancreatic Adenocarcinoma Cells – Role of Snail, Slug and Twist and Small Molecule Inhibitors

• Main Authors: Kaşıkcı E, Aydemir E, Bayrak ÖF, Şahin F
• Format: Article
• Language: English
• Published: Dove Medical Press 2020-06-01
• Series: OncoTargets and Therapy
• Subjects: pancreatic cancer; metastasis; cancer; emt; gene therapy; anti-cancer drug
• Online Access: https://www.dovepress.com/inhibition-of-migration-invasion-and-drug-resistance-of-pancreatic-ade-peer-reviewed-article-OTT

Ezgi Kaşıkcı,1,2 Esra Aydemir,1 Ömer Faruk Bayrak,3 Fikrettin Şahin1 1Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Istanbul 34755, Turkey; 2Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; 3Department of Medical Genetics, Yeditepe University Medical School and Yeditepe University Hospital, Istanbul 34718, TurkeyCorrespondence: Ezgi Kaşıkcı Email [e-mail]: The main purpose of this study is to demonstrate the effects of epithelial to mesenchymal transition activating transcription factor silencing (EMT-ATF silencing) on migration, invasion, drug resistance and tumor-forming abilities of various pancreatic cancer cell lines. Additionally, the contribution of small molecule inhibitors of EMT (SD-208 and CX4945) to the effects of gene silencing was evaluated.Methods: EMT activating transcription factors “Snail, Slug and Twist” were silenced by short hairpins on Panc-1, MIA PaCa-2, BxPC-3, and AsPC-1 pancreatic cancer cell lines. The changes in migration, invasion, laminin attachment, cancer stem-like cell properties and tumor-forming abilities were investigated. Chemosensitivity assays and small molecule inhibitors of EMT were applied to the metastatic pancreatic cancer cell line AsPC-1.Results: EMT-ATF silencing reduced EMT and stem cell-like characteristics of pancreatic cancer cell lines. Following EMT-ATF silencing amongst the four PC cell lines, AsPC-1 showed the best response and was chosen for further chemoresistance and combinational therapy applications. EMT downregulated AsPC-1 cells showed less resistance to select chemotherapeutics compared to the control group. Both small molecule inhibitors enhanced the outcomes of EMT-ATF silencing.Conclusion: Overall it was found that EMT-ATF silencing, either by EMT-ATF silencing or with the enhancement by small molecules, is a good candidate to treat pancreatic cancer since it simultaneously minimizes metastasis, stem cell properties, and drug resistance.Keywords: pancreatic cancer, metastasis, cancer, EMT, gene therapy, anti-cancer drug