Akt2 and nucleophosmin/B23 function as an oncogenic unit in human lung cancer cells
Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea Experimental Cell Research
(Impact Factor: 3.25).
12/2010; 317(7):966-75. DOI: 10.1016/j.yexcr.2010.12.013
The signaling network of protein kinase B(PKB)/Akt has been implicated in survival of lung cancer cells. However, understanding the relative contribution of the different isoform of Akt network is nontrival. Here, we report that Akt2 is highly expressed in human lung adenocarcinoma cell line A549 cells. Suppression of Akt2 expression in A549 cells results in notable inhibition of cell poliferation, soft agar growth, and invasion, accompanying by a decrease of nucleophosmin/B23 protein. Overexpression of Akt1 restores cancerous growth of A549 cells in B23-knockdown (KD) cells while Akt2 overexpression did not restore proliferating potential in cells with downregulated B23, thus suggesting Akt2 requires B23 to drive proliferation of lung cancer cell. Loss of functional Akt2 and B23 has similar defects on cell proliferation, apoptotic resistance and cell cycle regulation, while loss of Akt1 has less defects on cell proliferation, survival and cell cycle progression in A549 cells. Moreover, overexpression of B23 rescues the proliferative block induced as a consequence of loss of Akt2. Thus our data suggest that Akt2/B23 functions as an oncogenic unit to drive tumorigenesis of A549 lung cancer cells.
Available from: Hua Guo
- "The MTT and BrdU incorporation assay results showed that cells with NPM1 knockdown exhibited decreased cell proliferation (Figures 2B and 3C) and decreased PCNA expression (Figure 3D). This finding indicated that NPM1 function was inhibited in HCT116 cells, consistent with previous reports [30-32]. "
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ABSTRACT: We aimed to examine the expression level of Nucleophosmin (NPM1) protein in colon cancer tissues and to investigate the potential role of NPM1 in the regulation of cell migration and invasiveness.
Immunohistochemical assay was performed to examine the expression pattern of NPM1 in 31 groups of colonic carcinoma samples, including colon tumors, adjacent normal tissues, and matched metastatic lymph nodes from the same patients. Small interfering RNA technique and exogenous expression of wild type NPM1 methods were used to further verify the function of NPM1.
High-expression of NPM1 correlates with lymph node metastasis (P = 0.0003) and poor survival rate of human colon cancer patients (P = 0.017). SiRNA-mediated reduction of NPM1 was also shown to inhibit the migration and invasiveness of metastatic colon cancer HCT116 cell line. In addition, the exogenous expression of NPM1 in HT29 cells, a NPM1 low expression and low invasive colon cancer cell line, enhanced cell migration and invasiveness along with increased cell proliferation.
The current study uncovered the critical role of NPM1 in the regulation of colon cancer cells migration and invasion, and NPM1 may serve as a potential marker for the prognosis of colon cancer patients.
Journal of Biomedical Science 05/2012; 19(1):53. DOI:10.1186/1423-0127-19-53 · 2.76 Impact Factor
Available from: Manijeh Pasdar
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ABSTRACT: Nucleophosmin (NPM) is a nucleolar phosphoprotein that is involved in many cellular processes and has both oncogenic and growth suppressing activities. NPM is localized primarily in nucleoli but shuttles between the nucleus and the cytoplasm, and sustained cytoplasmic distribution contributes to its tumor promoting activities. Plakoglobin (PG, γ-catenin) is a homolog of β-catenin with dual adhesive and signaling functions. These proteins interact with cadherins and mediate adhesion, while their signaling activities are regulated by association with various intracellular partners. Despite these similarities, β-catenin has a well-defined oncogenic activity, whereas PG acts as a tumor/metastasis suppressor through unknown mechanisms. Comparison of the proteomic profiles of carcinoma cell lines with low- or no PG expression with their PG-expressing transfectants has identified NPM as being upregulated upon PG expression. Here, we examined NPM subcellular distribution and in vitro tumorigenesis/metastasis in the highly invasive and very low PG expressing MDA-MB-231 (MDA-231) breast cancer cells and their transfectants expressing increased PG (MDA-231-PG) or NPM shRNA (MDA-231-NPM-KD) or both (MDA-231-NPM-KD+PG). Increased PG expression increased the levels of nucleolar NPM and coimmunoprecipitation studies showed that NPM interacts with PG. PG expression or NPM knockdown decreased the growth rate of MDA-231 cells substantially and this reduction was decreased further in MDA-231-NPM-KD+PG cells. In in vitro tumorigenesis/metastasis assays, MDA-231-PG cells showed substantially lower and MDA-231-NPM-KD cells substantially higher invasiveness relative to the MDA-231 parental cells, and the co-expression of PG and NPM shRNA led to even further reduction of the invasiveness of MDA-231-PG cells. Furthermore, examination of the levels and localization of PG and NPM in primary biopsies of metastatic infiltrating ductal carcinomas revealed coordinated expression of PG and NPM. Together, the data suggest that PG may regulate NPM subcellular distribution, which may potentially change the function of the NPM protein from oncogenic to tumor suppression.
Oncogenesis 03/2012; 1(3):e4. DOI:10.1038/oncsis.2012.4 · 3.95 Impact Factor
Available from: Wei-sheng Feng
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ABSTRACT: Diabetes mellitus is a serious disease with metabolic disorders characterized by hyperglycaemia, and it is caused by complete or relative insufficiency of insulin secretion and/or insulin action. Therefore, clarifying the action mechanisms of insulin will help to research and develop the hypoglycemic and anti-diabetic agents. The PI3K/PKB signal pathway is extremely important in insulin actions, because it is involved in glucose transport, the inhibition of lipolysis, glycogen, protein and lipid synthase, the cell differentiation, proliferation and apoptosis, and other activities caused by insulin stimulation. In this paper, we reviewed the recent researches on the mechanism of insulin-stimulated PI3K/PKB signal transduction.
Chinese Journal of New Drugs 12/2012; 21(23):2763-2770.
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