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. Issue 12 (2nd December 2018)

• Record Type: Journal Article
• Authors: Crassini, Kyle; Pyke, Tahni; Shen, Yandong; Stevenson, William S.; Christopherson, Richard I.; Mulligan, Stephen P.; Best, Oliver Giles
• Is Part Of: Leukemia & lymphoma. Volume 59:Issue 12(2018)
• Page Start: 2917
• Page End: 2928
• Publication Date: 2018-12-02
• Subjects: CLL -- microenvironment -- locostatin; Leukemia -- Periodicals; Lymphomas -- Periodicals; 616.99419
• DOI: 10.1080/10428194.2018.1455974
• Languages: English
• ISSNs: 1042-8194

Abstract

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.