cx-4945 and Neoplasm-Metastasis

Endothelin-1 is a mitogenic peptide that activates several proliferation, survival, and invasiveness pathways. The effects of endothelin-1 rely on its activation by endothelin-converting enzyme-1 (ECE1), which is expressed as four isoforms with different cytoplasmic N termini. Recently, isoform ECE1c has been suggested to have a role in cancer aggressiveness. The N terminus of ECE1c is phosphorylated by protein kinase CK2 (also known as casein kinase 2), and this enhances its stability and promotes invasiveness in colorectal cancer cells. However, it is not known how phosphorylation improves stability and why this is correlated with increased aggressiveness. We hypothesized that CK2 phosphorylation protects ECE1c from N-terminal ubiquitination and, consequently, from proteasomal degradation. Here, we show that lysine 6 is the bona fide residue involved in ubiquitination of ECE1c and its mutation to arginine (ECE1c

Topics: Animals; Carcinogenesis; Casein Kinase II; Cell Line, Tumor; Colorectal Neoplasms; Endothelin-Converting Enzymes; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Mutation; Naphthyridines; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplastic Stem Cells; Phenazines; Phosphorylation; Prognosis; Protein Stability; Recombinant Proteins; Up-Regulation; Xenograft Model Antitumor Assays