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

Kyle Crassini, Tahni Pyke, Yandong Shen, William S. Stevenson, Richard I. Christopherson, Stephen P. Mulligan, Oliver G. Best

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)2917-2928
Number of pages12
JournalLeukemia & lymphoma
Volume59
Issue number12
DOIs
Publication statusPublished - 2018
Externally publishedYes

Keywords

  • 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 *cll *locostatin *microenvironment
  • microenvironment
  • CLL
  • locostatin

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