Colon cancer cell invasion is promoted by protein kinase CK2 through increase of endothelin-converting enzyme-1c protein stability
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Ignacio Niechi1, Eduardo Silva1, Pablo Cabello1, Hernan Huerta1, Valentina Carrasco1, Paulina Villar1, Luis Rodrigo Cataldo1, Katherine Marcelain2, Ricardo Armisen2, Manuel Varas-Godoy3, Cristina Fernandez4, Julio C. Tapia1,2
1Cell Transformation Laboratory, Program of Cellular and Molecular Biology, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile
2ICBM, Faculty of Medicine, University of Chile, Santiago, Chile
3Fundacion Ciencia y Vida, Santiago, Chile
4Department of Anatomopathology, HCUCH, Faculty of Medicine, University of Chile, Santiago, Chile
Julio C. Tapia, e-mail: [email protected]
Keywords: CK2, ECE-1, endothelin, colon cancer, metastasis
Received: February 08, 2015 Accepted: October 06, 2015 Published: October 16, 2015
Endothelin-converting enzyme-1c (ECE-1c) is a membrane metalloprotease involved in endothelin-1 synthesis, which has been shown in vitro to have a role in breast, ovary and prostate cancer cell invasion. N-terminal end of ECE-1c displays three putative phosphorylation sites for the protein kinase CK2. We studied whether CK2 phosphorylates N-terminal end of ECE-1c as well as whether this has a role in migration and invasion of colon cancer cells. CK2 phosphorylated the N-terminal end of ECE-1c and this was precluded upon inhibition of CK2. Inhibition also led to diminished protein levels of both endogen ECE-1 or GFP-fused N-terminal end of ECE-1c in 293T embryonic and DLD-1 colon cancer cells, which highlighted the importance of this motif on UPS-dependent ECE-1c degradation. Full-length ECE-1c mutants designed either to mimic or abrogate CK2-phosphorylation displayed increased or decreased migration/invasion of colon cancer cells, respectively. Moreover, ECE-1c overexpression or its silencing with a siRNA led to increased or diminished cell migration/invasion, respectively. Altogether, these data show that CK2-increased ECE-1c protein stability is related to augmented migration and invasion of colon cancer cells, shedding light on a novel mechanism by which CK2 may promote malignant progression of this disease.
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