oxadiazoles and Cell-Transformation--Neoplastic

oxadiazoles has been researched along with Cell-Transformation--Neoplastic* in 3 studies

Other Studies

3 other study(ies) available for oxadiazoles and Cell-Transformation--Neoplastic

ArticleYear
IKBKE protein activates Akt independent of phosphatidylinositol 3-kinase/PDK1/mTORC2 and the pleckstrin homology domain to sustain malignant transformation.
    The Journal of biological chemistry, 2011, Oct-28, Volume: 286, Issue:43

    Serine/threonine kinase Akt regulates key cellular processes such as cell growth, proliferation, and survival. Activation of Akt by mitogenic factor depends on phosphatidylinositol 3-kinase (PI3K). Here, we report that IKBKE (also known as IKKε and IKKi) activates Akt through a PI3K-independent pathway. IKBKE directly phosphorylates Akt-Thr308 and Ser473 independent of the pleckstrin homology (PH) domain. IKBKE activation of Akt was not affected by inhibition of PI3K, knockdown of PDK1 or mTORC2 complex. Further, this activation could be inhibited by Akt inhibitors MK-2206 and GSK690693 but not the compounds (perifosine and triciribine) targeting the PH domain of Akt. Expression of IKBKE largely correlates with activation of Akt in breast cancer. Moreover, inhibition of Akt suppresses IKBKE oncogenic transformation. These findings indicate that IKBKE is an Akt-Thr308 and -Ser473 kinase and directly activates Akt independent of PI3K, PDK1, and mTORC2 as well as PH domain. Our data also suggest that Akt inhibitors targeting the PH domain have no effect on the tumors in which hyperactive Akt resulted from elevated IKBKE.

    Topics: 3-Phosphoinositide-Dependent Protein Kinases; Animals; Breast Neoplasms; Cell Line, Tumor; Cell Transformation, Neoplastic; Enzyme Activation; Female; Gene Deletion; HEK293 Cells; Heterocyclic Compounds, 3-Ring; Humans; I-kappa B Kinase; Mammary Neoplasms, Animal; Mice; Mice, Knockout; NIH 3T3 Cells; Oxadiazoles; Phosphatidylinositol 3-Kinases; Phosphorylation; Phosphorylcholine; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Proto-Oncogene Proteins c-akt; Ribonucleosides; Trans-Activators; Transcription Factors

2011
GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2010, Jan-15, Volume: 16, Issue:2

    Akt plays a central role in regulating tumor cell survival and cell cycle progression and is regarded as a promising therapeutic target. We used genetically defined mouse models that develop spontaneous tumors exhibiting activated Akt to determine if Akt inhibition by GSK690693 is effective in the treatment of cancer. The broad long-term objective of this project was to use preclinical cancer models with precisely defined genetic lesions to elucidate the efficacy of targeting Akt with GSK690693.. We tested the in vivo effects of GSK690693 in Lck-MyrAkt2 transgenic mice that develop lymphomas, heterozygous Pten(+/-) knockout mice that exhibit endometrial tumors, and TgMISIIR-TAg-DR26 mice that develop ovarian carcinomas, all of which exhibit hyperactivation of Akt. In addition to standard disease onset and histology, tumors arising in treated animals were examined by immunohistochemistry to verify downregulated Akt signaling relative to placebo-treated mice. When possible, drug response was evaluated in tumor cell cultures by standard proliferation and apoptosis assays and by immunoblotting with various phosphospecific antibodies.. GSK690693 exhibited efficacy irrespective of the mechanism of Akt activation involved. Interestingly, GSK690693 was most effective in delaying tumor progression in Lck-MyrAkt2 mice expressing a membrane-bound, constitutively active form of Akt. Both tumors and primary cell cultures displayed downregulation of the Akt pathway, increased apoptosis, and primarily decreased cell proliferation.. These results suggest that GSK690693 or other Akt inhibitors might have therapeutic efficacy in human cancers with hyperactivated Akt and/or a dependence on Akt signaling for tumor progression.

    Topics: Animals; Antineoplastic Agents; Cell Transformation, Neoplastic; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Enzyme Activation; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Mice; Mice, Transgenic; Neoplasm Transplantation; Neoplasms; Oncogene Protein v-akt; Oxadiazoles; Protein Kinase Inhibitors; Tumor Cells, Cultured

2010
Voltage-sensitive calcium channels in normal and transformed 3T3 fibroblasts.
    Science (New York, N.Y.), 1988, Feb-26, Volume: 239, Issue:4843

    Patch clamp recordings of whole-cell and single channel currents revealed the presence of two voltage-sensitive calcium channel types in the membrane of 3T3 fibroblasts. The two calcium channel types were identified by their unitary properties and pharmacological sensitivities. Both calcium channel types were present in all control 3T3 cells, but one type was selectively suppressed in 3T3 cells that had been transformed by activated c-H-ras, EJ-ras, v-fms, or polyoma middle T oncogenes. The presence of voltage-sensitive calcium channels in these nonexcitable cells and the control of their functional expression by transforming oncogenes raises questions about their role in the control of calcium-sensitive processes such as cell motility, cytoskeletal organization, and cell growth.

    Topics: Animals; Calcium; Calcium Channel Agonists; Cell Division; Cell Line; Cell Line, Transformed; Cell Transformation, Neoplastic; Electric Conductivity; Fibroblasts; Ion Channels; Kinetics; Membrane Potentials; Mice; Nicotinic Acids; Oncogenes; Oxadiazoles

1988