cx-4945 has been researched along with Colorectal-Neoplasms* in 2 studies
2 other study(ies) available for cx-4945 and Colorectal-Neoplasms
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Endothelin-converting enzyme-1c promotes stem cell traits and aggressiveness in colorectal cancer cells.
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 | 2020 |
CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells.
Protein kinase CK2 is a highly conserved and constitutively active Ser/Thr-kinase that phosphorylates a large number of substrates, resulting in increased cell proliferation and survival. A known target of CK2 is Akt, a player in the PI3K/Akt/mTORC1 signaling pathway, which is aberrantly activated in 32% of colorectal cancer (CRC) patients. On the other hand, mTORC1 plays an important role in the regulation of protein synthesis, cell growth, and autophagy. Some studies suggest that CK2 regulates mTORC1 in several cancers. The most recently developed CK2 inhibitor, silmitasertib (formerly CX-4945), has been tested in phase I/II trials for cholangiocarcinoma and multiple myeloma. This drug has been shown to induce autophagy and enhance apoptosis in pancreatic cancer cells and to promote apoptosis in non-small cell lung cancer cells. Nevertheless, it has not been tested in studies for CRC patients. We show in this work that inhibition of CK2 with silmitasertib decreases in vitro tumorigenesis of CRC cells in response to G2/M arrest, which correlates with mTORC1 inhibition and formation of large cytoplasmic vacuoles. Notably, molecular markers indicate that these vacuoles derive from massive macropinocytosis. Altogether, these findings suggest that an aberrantly elevated expression/activity of CK2 may play a key role in CRC, promoting cell viability and proliferation in untreated cells, however, its inhibition with silmitasertib promotes methuosis-like cell death associated to massive catastrophic vacuolization, accounting for decreased tumorigenicity at later times. These characteristics of silmitasertib support a potential therapeutic use in CRC patients and probably other CK2-dependent cancers. Topics: Carcinogenesis; Casein Kinase II; Cell Cycle Checkpoints; Cell Death; Cell Movement; Cell Survival; Colorectal Neoplasms; HCT116 Cells; HT29 Cells; Humans; Naphthyridines; Phenazines; Pinocytosis; Protein Kinase Inhibitors; Transfection; Vacuoles | 2019 |