Protein kinase A as a biological target in cancer therapy

Naviglio, Silvio; Caraglia, Michele; Abbruzzese, Alberto; Chiosi, Emilio; Gesto, Davide Di; Marra, Monica; Romano, Maria; Sorrentino, Angela; Sorvillo, Luca; Spina, Annamaria; Illiano, G.

doi:10.1517/14728220802602349

Cited by 84 publications

(50 citation statements)

References 78 publications

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“…We then end up with a model where PKA controls the level and the localization of KCNA1. Regulation of the tumor-suppressive function of KCNA1 in this study by the PKA, which is considered to be a possible target for cancer therapy due to its involvement in tumor initiation and progression in numerous cancers (39), suggests that targeting PKA in cancer may activate the KCNA1 tumor-suppressive pathway.…”

Section: Discussionmentioning

confidence: 70%

Potassium Channel KCNA1 Modulates Oncogene-Induced Senescence and Transformation

et al. 2013

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Oncogene-induced senescence (OIS) constitutes a failsafe program that restricts tumor development. However, the mechanisms that link oncogenesis to senescence are not completely understood. We carried out a loss-of-function genetic screen that identified the potassium channel KCNA1 as a determinant of OIS escape that can license tumor growth. Oncogenic stress triggers an increase in KCNA1 expression and its relocation from the cytoplasm to the membrane. Mechanistically, this relocation is due to a loss of protein kinase A (PKA)-induced phosphorylation at residue S446 of KCNA1. Accordingly, sustaining PKA activity or expressing a KCNA1 phosphomimetic mutant maintained KCNA1 in the cytoplasm and caused escape from OIS. KCNA1 relocation to the membrane induced a change in membrane potential that invariably resulted in cellular senescence. Restoring KCNA1 expression in transformation-competent cells triggered variation in membrane potential and blocked RAS-induced transformation, and PKA activation suppressed both effects. Furthermore, KCNA1 expression was reduced in human cancers, and this decrease correlated with an increase in breast cancer aggressiveness. Taken together, our results identify a novel pathway that restricts oncogenesis through a potassium channel-dependent senescence pathway. Cancer Res; 73(16); 5253-65. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 70%

Potassium Channel KCNA1 Modulates Oncogene-Induced Senescence and Transformation

et al. 2013

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“…This indicates that the free catalytic subunit in the nucleus constitutes a form of PKAc that is subject to regulation by Syk. The effects of elevated cAMP on cells are pleiotropic and context-dependent (43,44). An association of active PKA with reduced cell growth can occur through the phosphorylation of CREB and enhancement of specific gene transcription and via the direct phosphorylation of various regulators of cell growth and survival such as Raf-1, Bim, and Par-4 (45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Syk Inhibits the Activity of Protein Kinase A by Phosphorylating Tyrosine 330 of the Catalytic Subunit

Huang

Iliuk

et al. 2013

Journal of Biological Chemistry

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“…Hematological malignancies, including large B cell lymphoma and chronic lymphocytic leukemia, are associated with a deficiency in apoptosis (10, 11). We and others have implicated the cAMP/PKA pathway as a promising one to enhance killing of lymphoma and leukemia cells (7,8,(12)(13)(14). Despite the proapoptotic ability of cAMP/PKA, the mechanisms for this action are poorly defined.…”

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confidence: 99%

Increased Expression of the Pro-apoptotic Protein BIM, a Mechanism for cAMP/Protein Kinase A (PKA)-induced Apoptosis of Immature T Cells

Zambon

Wilderman

et al. 2011

Journal of Biological Chemistry

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The second messenger cAMP is proapoptotic for numerous cell types, but the mechanism for this proapoptotic action is not defined. Here, we use murine CD4 ؉ /CD8 ؉ S49 lymphoma cells and isolated thymocytes to assess this mechanism. In WT Apoptosis, programmed cell death, contributes to a variety of cellular processes that include embryonic development, tissue homeostasis, and immune responses. Apoptosis can be stimulated by a variety of "death stimuli," including DNA damage, oxidative stress, hormones, cytokines, and drugs and is often targeted in cancer therapy. The second messenger cAMP has cell type-dependent effects on apoptosis (as recently reviewed (1)), being anti-apoptotic in certain cell types (e.g. neutrophils (2), eosinophils (3), hepatocytes (4), gastrointestinal epithelial cells (5), and several others) whereas having proapoptotic actions in other types of cells (e.g. cardiac myocytes (6) and certain lymphoid cells (7), in particular poorly differentiated lymphoblastic cells (8, 9)). Hematological malignancies, including large B cell lymphoma and chronic lymphocytic leukemia, are associated with a deficiency in apoptosis (10, 11). We and others have implicated the cAMP/PKA pathway as a promising one to enhance killing of lymphoma and leukemia cells (7,8,(12)(13)(14). Despite the proapoptotic ability of cAMP/PKA, the mechanisms for this action are poorly defined.Using murine S49 lymphoma cells, CD4 ϩ /CD8 ϩ T cells that undergo growth arrest in the G 1 phase of the cell cycle and apoptosis in response to cAMP-promoted activation of PKA 2 (15), we identified mRNAs that differ between WT and kin-S49 cells, which lack PKA (16). In other studies, we showed that expression of certain apoptotic pathway members are differentially regulated in WT and cAMP-deathless (D-) S49 cells (7, 12), a clonal isolate that undergoes G 1 arrest but is resistant to cAMP/PKA-promoted apoptosis (17).The proapoptotic protein Bim, a BH3-only Bcl family member protein, shows a pronounced difference in expression between 12), with Bim expression being higher and longer in the WT cells treated with a cAMP analog or with a ␤-adrenergic agonist; moreover, increase in cAMP does not increase Bim expression in kin-cells (7,12). Bim triggers apoptosis by promoting the release of cytochrome C from mitochondria. However, Bim may not be sufficient for inducing apoptosis, which can involve other BH3-only proteins (18). Multiple Bim isoforms exist (19), certain of which have been implicated in promoting T cell and B cell apoptosis (20). In this study, we used S49 cells (WT, D-, and kin-mutants) and CD4 ϩ / CD8 ϩ thymocytes isolated from WT and Bim Ϫ/Ϫ mice to test whether Bim mediates cAMP/PKA-promoted apoptotic cell death in CD4 ϩ /CD8 ϩ cells. EXPERIMENTAL PROCEDURESMaterials-WT, kin-, and D-S49 cells were obtained from the University of San Francisco cell culture facility. 8-(4-chlorophenylthio)-adenosine-3Ј,5Ј-cyclic monophosphate (CPTcAMP) was obtained from Sigma-Aldrich. BimL cDNA was purchased from Addgene (21). Protease inhibitor m...

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Protein kinase A as a biological target in cancer therapy

Cited by 84 publications

References 78 publications

Potassium Channel KCNA1 Modulates Oncogene-Induced Senescence and Transformation

Potassium Channel KCNA1 Modulates Oncogene-Induced Senescence and Transformation

Syk Inhibits the Activity of Protein Kinase A by Phosphorylating Tyrosine 330 of the Catalytic Subunit

Increased Expression of the Pro-apoptotic Protein BIM, a Mechanism for cAMP/Protein Kinase A (PKA)-induced Apoptosis of Immature T Cells

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