Inhibition of the Raf-1 kinase inhibitory protein (RKIP) by locostatin induces cell death and reduces the CXCR4-mediated migration of chronic lymphocytic leukemia cells.

Abstract	The Raf-1 kinase inhibitory protein (RKIP) is an important regulatory element in multiple signaling pathways, including MAPK-ERK1/2. We investigated whether targeted disruption of RKIP is a therapeutic option for chronic lymphocytic leukemia (CLL). The RKIP inhibitor locostatin-induced apoptosis of CLL cells, irrespective of poor prognostic indications or treatment history. Locostatin down-regulated MAPK-ERK1/2 and AKT phosphorylation, decreased expression of the chemokine receptor CXCR4 (p = .04) and reduced the migratory capacity of CLL cells toward stroma-derived factor 1α (SDF-1α, p = .02). Immuno-blotting and immuno-precipitation showed that RKIP is constitutively phosphorylated and highly expressed in CLL cells and that the actions of locostatin may be mediated by binding of G-protein receptor kinase-2 (GRK2) to MEK1 and AKT. Collectively, our data suggest that inhibition of RKIP may be effective against CLL, reducing the survival and migratory capacity of the leukemic cells through down-regulation of MAPK-ERK1/2 and AKT-mediated signaling.
Authors	Kyle Crassini, Tahni Pyke, Yandong Shen, William S Stevenson, Richard I Christopherson, Stephen P Mulligan, Oliver Giles Best
Journal	Leukemia & lymphoma (Leuk Lymphoma) Vol. 59 Issue 12 Pg. 2917-2928 (12 2018) ISSN: 1029-2403 [Electronic] United States
PMID	29911936 (Publication Type: Journal Article)
Chemical References	CXCR4 protein, human Oxazolidinones PEBP1 protein, human Phosphatidylethanolamine Binding Protein Receptors, CXCR4 locostatin
Topics	Apoptosis (drug effects) Cell Line, Tumor Cell Movement (drug effects) Cell Survival (drug effects) Down-Regulation Drug Screening Assays, Antitumor Humans Leukemia, Lymphocytic, Chronic, B-Cell (blood, drug therapy, pathology) Leukocytes, Mononuclear MAP Kinase Signaling System (drug effects) Oxazolidinones (pharmacology, therapeutic use) Phosphatidylethanolamine Binding Protein (antagonists & inhibitors, metabolism) Phosphorylation (drug effects) Primary Cell Culture Receptors, CXCR4 (metabolism)

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