Abstract
BackgroundCCN1 plays distinct roles in various tumor types, but little is known regarding the role of CCN1 in leukemia.MethodsWe analyzed CCN1 protein expression in leukemia cell lines and in AML bone marrow samples. We also evaluated the effects of antibody- or siRNA-mediated inhibition of CCN1 on the growth of two AML cell lines (U937 and Kasumi-1 cells) and on the MEK/ERK pathway, β-catenin and other related genes.ResultsU937 and Kasumi-1 cells had markedly higher CCN1 expression than the 5 other leukemia cell lines, and CCN1 protein expression was higher in the AML bone marrow samples than in the normal bone marrow samples. Blocking CCN1 with an antibody in U937 and Kasumi-1 cells suppressed proliferation, increased apoptosis, down-regulated Bcl-xL and c-Myc expression, up-regulated Bax expression, and had no effect on Survivin. siRNA-mediated down-regulation of CCN1 inhibited the proliferation and colony formation of U937 and Kasumi-1 cells and increased cytarabine-induced apoptosis. Furthermore, CCN1 siRNA reduced MEK and ERK phosphorylation without affecting β-catenin; the CCN1 antibody similarly affected MEK and ERK phosphorylation. These changes in phosphorylation could influence the expression of Bcl-xL, c-Myc and Bax in AML cells.ConclusionsThe data suggested that CCN1 is a tumor promoter in AML that acts through the MEK/ERK pathway to up-regulate c-Myc and Bcl-xL and to down-regulate Bax.
Highlights
CCN1 plays distinct roles in various tumor types, but little is known regarding the role of CCN1 in leukemia
We previously showed that CCN1 is a direct target of β-catenin signaling in hepatocellular carcinoma (HCC), where it may be important for cancer progression [13]
Our results showed that CCN1 was overexpressed in two acute myeloid leukemia (AML) cell lines (U937 and Kasumi-1) and in AML bone marrow samples
Summary
CCN1 plays distinct roles in various tumor types, but little is known regarding the role of CCN1 in leukemia. Domains within the CCN1 protein have binding sites for the various integrins or heparan sulfate proteoglycans (HSPGs) on different cell types, where they activate distinct signaling pathways. CCN1 plays unique roles in different tumor types: it is an oncogenic factor for cancers of the breast [3], prostate [4], and stomach [5] as well as for glioma [6], esophageal squamous cell carcinoma [7], and chondrosarcoma [8]. Extracellular signal-regulated kinase (ERK), a member of the MAP kinase family, can be phosphorylated and activated by MEK (mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase). Inhibition of MEK or ERK suppresses AML cell growth and induces apoptosis [19,20,21]
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