Fendiline inhibits proliferation and invasion of pancreatic cancer cells by interfering with ADAM10 activation and β-catenin signaling
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Neha Woods1, Jose Trevino2, Domenico Coppola3, Srikumar Chellappan4, Shengyu Yang5 and Jaya Padmanabhan1
1 Department of Molecular Medicine, University of South Florida, Tampa, FL, USA
2 Department of Surgery, Colleges of Medicine, Dentistry, and Public Health and Health Professions, University of Florida Health Science Center, Gainesville, Florida, USA
3 Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Magnolia Drive, Tampa, FL, USA
4 Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Magnolia Drive, Tampa, FL, USA
5 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
Jaya Padmanabhan, email:
Keywords: pancreatic cancer, calcium signaling, ADAM10, cadherins, β-catenin
Received: June 29, 2015 Accepted: September 14, 2015 Published: September 30, 2015
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.
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