Abstract
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.
Highlights
Endothelin-1 (ET-1) is a vasoactive peptide that has been shown to have a role in cancer [1]
Evidence found in the literature sustains that ET-1 is a β-catenin target that participate in an autocrine fashion by up-regulating this signaling pathway, as well as by promoting traits associated with metastasis [19]
An in silico analysis of the promoter region of Endothelin-converting enzyme-1c (ECE-1c) performed in our group showed a putative Wnt response element (WRE) −455 bp from the start site +1
Summary
Endothelin-1 (ET-1) is a vasoactive peptide that has been shown to have a role in cancer [1]. Big-ET-1 is secreted into the extracellular media where is processed by the endothelin-converting enzyme-1 (ECE-1) to produce ET-1, the bioactive form of 21 residues [4]. ECE-1c is mainly expressed in non-tumor and tumor cells but, importantly, is the unique isoform up-regulating invasion in prostate [8] and breast cancer cells [8,9,10]. This suggests that the www.impactjournals.com/oncotarget role of ECE-1c in cancer cell invasion depends of its cytoplasmic N-terminal end. N-terminal end of ECE-1c displays three putative phosphorylation sites for protein kinase CK2, namely threonine-9, serine-18 and serine-20
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