title: Fendiline inhibits proliferation and invasion of pancreatic cancer cells by interfering with ADAM10 activation and β-catenin signaling.
abstract: ADAM10 (A Disintegrin and Metalloprotease Domain 10) affects the pathophysiology of various cancers, and we had shown that inhibition of ADAM10 sensitizes pancreatic cancer cells to gemcitabine. ADAM10 is activated in response to calcium influx, and here we examined if calcium channel blockers (CCB) would impede ADAM10 activation and affect biology of pancreatic cancer cells. We find that the CCB, fendiline, significantly reduces proliferation, migration, invasion, and anchorage independent growth of pancreatic cancer cells. This was associated with ADAM10 inhibition and its localization at the actin-rich membrane protrusions. Further, fendiline-treated cells formed cadherin-catenin positive tight adherens junctions and elicited defective protein trafficking and recycling. Furthermore, the expression of β-catenin target genes, cyclinD1, c-Myc and CD44, were significantly decreased, suggesting that fendiline might prevent cell proliferation and migration by inhibiting ADAM10 function, cadherin proteolysis and stabilization of cadherin-catenin interaction at the plasma membrane. This will subsequently diminish β-catenin intracellular signaling and repress TCF/LEF target gene expression. Supporting this notion, RNAi-directed downregulation of ADAM10 in cancer cells decreased the expression of cyclinD1, c-Myc and CD44. Furthermore, analysis of human pancreatic tumor tissue microarrays and lysates showed elevated levels of ADAM10, suggesting that aberrant activation of ADAM10 plays a fundamental role in growth and metastasis of PDACs and inhibiting this pathway might be a viable strategy to combat PDACs.
authors.affiliation: Department of Molecular Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Neha
authors.initials: N
authors.lastname: Woods
authors.affiliation: Department of Surgery, Colleges of Medicine, Dentistry, and Public Health and Health Professions, University of Florida Health Science Center, Gainesville, FL, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Trevino
authors.affiliation: Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Magnolia Drive, Tampa, FL, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.affiliation: Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Magnolia Drive, Tampa, FL, USA.
authors.forename: Srikumar
authors.initials: S
authors.lastname: Chellappan
authors.affiliation: Comprehensive Melanoma Research Center, Department of Tumor Biology, Department of Molecular Oncology, Department of Cutaneous Oncology, Experimental Therapeutics Laboratory, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Shengyu
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Molecular Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Jaya
authors.initials: J
authors.lastname: Padmanabhan
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005275:Fendiline / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D008565:Membrane Proteins; D051176:beta Catenin; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D005275:Fendiline
keywords: ADAM10; cadherins; calcium signaling; pancreatic cancer; β-catenin