PUBLICATION

"JANUS" EFFICACY OF CX-5011: CK2 INHIBITION AND METHUOSIS INDUCTION BY INDEPENDENT MECHANISMS

Authors
D'Amore, C., Moro, E., Borgo, C., Itami, K., Hirota, T., Pinna, L.A., Salvi, M.
ID
ZDB-PUB-200804-8
Date
2020
Source
Biochimica et biophysica acta. Molecular cell research   1867(11): 118807 (Journal)
Registered Authors
Moro, Enrico
Keywords
CK2, cancer, cell death, kinase inhibitors, macropinocytosis, methuosis
MeSH Terms
  • CRISPR-Cas Systems/genetics
  • Casein Kinase II/antagonists & inhibitors
  • Casein Kinase II/genetics*
  • Cell Death/drug effects
  • Cell Death/genetics*
  • Gene Editing
  • Hep G2 Cells
  • Humans
  • Indoles/pharmacology
  • Neoplasms/drug therapy*
  • Pinocytosis/drug effects
  • Pinocytosis/genetics
  • Pyrimidines/pharmacology
  • Quinolines/pharmacology
  • Vacuoles/drug effects
  • Vacuoles/genetics
  • rac1 GTP-Binding Protein/antagonists & inhibitors
  • rac1 GTP-Binding Protein/genetics*
PubMed
32745724 Full text @ BBA Molecular Cell Research
Abstract
Methuosis has been described as a distinctive form of cell death characterized by the displacement of large fluid-filled vacuoles derived from uncontrolled macropinocytosis. Its induction has been proposed as a new strategy against cancer cells. Small molecules, such as indole-based calchones, have been identified as methuosis inducers and, recently, the CK2 inhibitor CX-4945 has been shown to have a similar effect on different cell types. However, the contribution of protein kinase CK2 to methuosis signalling is still controversial. Here we show that methuosis is not related to CK2 activity since it is not affected by structurally unrelated CK2 inhibitors and genetic reduction/ablation of CK2 subunits. Interestingly, CX-5011, a CK2 inhibitor related to CX-4945, behaves as a CK2-independent methuosis inducer, four times more powerful than its parental compound and capable to promote the formation on enlarged cytosolic vacuoles at low micromolar concentrations. We show that pharmacological inhibition of the small GTPase Rac-1, its downregulation by siRNA treatment, or the over-expression of the dominant-negative mutated form of Rac-1 (Rac-1 T17N), impairs CX-5011 ability to induce methuosis. Furthermore, cell treatment with CX-5011 induces a durable activation of Rac-1 that persists for at least 24 hours. Worthy of note, CX-5011 is able to promote macropinocytosis not only in mammalian cells, but also in an in-vivo zebrafish model. Based on these evidences, CX-5011 is, therefore, proposed as a potential promising compound for cancer therapies for its dual efficacy as an inhibitor of the pro-survival kinase CK2 and inducer of methuosis.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping