Koseoglu S, Lu Z, Kumar C, Kirschmeier P, Zou JAKT1, AKT2 and AKT3-dependent cell survival is cell line-specific and knockdown of all three isoforms selectively induces apoptosis in 20 human tumor cell lines. Cancer Biol Therapy 6(5): 755-762

Department of Tumor Biology, Schering-Plough Research Institute, Kenilworth, New Jersey, USA.
Cancer biology & therapy (Impact Factor: 3.07). 05/2007; 6(5):755-62. DOI: 10.4161/cbt.6.5.3995
Source: PubMed


AKT is a key serine/threonine kinase in the PTEN/PI3K/AKT pathway(1) and activationof AKT is often observed in human cancers. To explore the role of AKT in cell survival in different tumor cells, we tested 20 human tumor cell lines for response to knockdown of AKT by small interference RNA (siRNA) and/or a kinase-dead mutant AKT. siRNA-mediated knockdown of all three AKT isoforms in tumor cell lines led to a reduction of phosphorylation of AKT substrates. Knockdown of AKT resulted in apoptosis in six out of 11 tumor cells with activated AKT. In contrast, knockdown of AKT induced apoptosis in three out of nine cell lines with a low level of active AKT. The responsiveness of the cells to knockdown of AKT was not affected by mutational status of p53 but appeared correlated with overexpression of HER2. To assess the role of individual AKT isoforms, five of the cell lines responsive to knockdown of AKT were further characterized. In ZR-75 cells, AKT1 is the predominant isoform responsible for cell proliferation and survival. Conversely, in IGROV1 cells, AKT2 plays a major role in cell proliferation, but no single isoform is essential for cell survival. Thus, the relative importance of the AKT isoforms is cell line-specific. Our data suggest that inhibiting all three AKT isoforms is necessary to elicit maximal apoptotic response in tumor cells, and the level of activated AKT is a favorable but not always reliable biomarker for preselection of responsive tumor cell lines to AKT inhibitors.

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Available from: Paul Kirschmeier, Dec 20, 2013
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    • "Opel et al. [46] reported that the inhibition of PI3K is an efficient strategy to sensitize glioblastoma cells to the induction of apoptosis. Koseoglu et al. [47] analyzed the influence of AKT1, AKT2, and AKT3 knockdown on the induction of apoptosis in 20 human tumor cell lines and found that the knockdown of AKT resulted in apoptosis in six out of 11 tumor cell lines with activated AKT. Stahl et al. [48] recorded that a targeted reduction in the AKT3 expression with siRNA stimulates apoptosis and inhibits the development of melanoma tumors. "
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    ABSTRACT: Glioblastoma multiforme (GBM) is the most malignant and invasive human brain tumor that is difficult to treat and has a very poor prognosis. Thus, new therapeutic strategies that target GBM are urgently needed. The PI3K/AKT/PTEN signaling pathway is frequently deregulated in a wide range of cancers. The present study was designed to examine the inhibitory effect of AKT3 or PI3KCA siRNAs on GBM cell growth, viability, and proliferation.T98G cells were transfected with AKT3 and/or PI3KCA siRNAs. AKT3 and PI3KCA protein-positive cells were identified using FC and Western blotting. The influence of specific siRNAs on T98G cell viability, proliferation, cell cycle, and apoptosis was evaluated as well using FC. Alterations in the mRNA expression of AKT3, PI3KCA, and apoptosis-related genes were analyzed using QRT-PCR. Knockdown of AKT3 and/or PI3KCA genes in T98G cells led to a significant reduction in cell viability, the accumulation of subG1-phase cells and, a reduced fraction of cells in the S and G2/M phases. Additionally, statistically significant differences in the BAX/BCL-2 ratio and an increased percentage of apoptotic cells were found. The siRNA-induced AKT3 and PI3KCA mRNA knockdown may offer a novel therapeutic strategy to control the growth of human GBM cells.
    Full-text · Article · May 2014 · BioMed Research International
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    • "AKT isoform knockout mice have shown that suppression of AKT1 induces a reduction of body and cell size, AKT2 knockouts show diabetes mellitus-like syndrome, and AKT3 deletion causes smaller brain size and corpus callosum disorganization [8, 9]. Variations in AKT expression patterns, mutations, and roles of different isoforms have been observed in various cancer cell lines [10]. AKT1 may function as an oncogene and AKT3 as a tumor suppressor [11], and AKT mutations have been detected in human colorectal cancer (AKT2) and lung tumors (AKT1 and AKT3). "
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    ABSTRACT: In response to ionizing radiation, several signaling cascades in the cell are activated to repair the DNA breaks, prevent apoptosis, and keep the cells proliferating. AKT is important for survival and proliferation and may also be an activating factor for DNA-PKcs and MRE11, which are essential proteins in the DNA repair process. AKT (PKB) is hyperactivated in several cancers and is associated with resistance to radiotherapy and chemotherapy. There are three AKT isoforms (AKT1, AKT2, and AKT3) with different expression patterns and functions in several cancer tumors. The role of AKT isoforms has been investigated in relation to radiation response and their effects on DNA repair proteins (DNA-PKcs and MRE11) in colon cancer cell lines. The knockout of AKT1 and/or AKT2 affected the radiation sensitivity, and a deficiency of both isoforms impaired the rejoining of radiation-induced DNA double strand breaks. Importantly, the active/phosphorylated forms of AKT and DNA-PKcs associate and exposure to ionizing radiation causes an increase in this interaction. Moreover, an increased expression of both DNA-PKcs and MRE11 was observed when AKT expression was ablated, yet only DNA-PKcs expression influenced AKT phosphorylation. Taken together, these results demonstrate a role for both AKT1 and AKT2 in radiotherapy response in colon cancer cells involving DNA repair capacity through the nonhomologous end joining pathway, thus suggesting that AKT in combination with DNA-PKcs inhibition may be used for radiotherapy sensitizing strategies in colon cancer. Electronic supplementary material The online version of this article (doi:10.1007/s13277-013-1465-9) contains supplementary material, which is available to authorized users.
    Full-text · Article · Dec 2013 · Tumor Biology
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    • "Three Akt isoforms, Akt-1, Akt-2, and Akt-3 are encoded by the genes PKBα, PKBβ and PKBγ, respectively (Scheid and Woodgett, 2001). Akt-1 is involved in cellular survival, cell proliferation and protein synthesis pathway, Akt-2 is an important signaling molecule in cell proliferation (Koseoglu et al., 2007) however, the role of Akt-3 is not clear. "
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    ABSTRACT: Serine/threonine protein kinase v-akt murine thymoma viral oncogene homolog (Akt) is one of the survival kinases with multiple biological functions in the brain and throughout the body. Schizophrenia is one of the most devastating psychiatric disorders. Accumulating evidence has indicated the involvement of the Akt signaling pathway in the pathogenesis of this disorder. Genetic linkage and association studies have identified Akt-1 as a candidate susceptibility gene related for schizophrenia. The level of Akt-1 protein and its kinase activity decreased significantly both in white blood cells from schizophrenic patients and in postmortem brain tissue of schizophrenic patients. Consistent with these findings, alterations in the upstream and downstream pathways of Akt have also been found in many psychiatric disorders. Furthermore, both typical and atypical antipsychotic drugs modify the Akt signaling pathway in a variety of conditions relative to schizophrenia. In addition as a survival kinase, Akt participates in neurodevelopment, synaptic plasticity, protein synthesis and neurotransmission in the central nervous system. It is thought that reduced activity of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway could at least partially explain the cognitive impairment, synaptic morphologic abnormality, neuronal atrophy and dysfunction of neurotransmitter signaling in schizophrenia. In addition, reduced levels of Akt may increase the effects of risk factors on neurodevelopment, attenuate the effects of growth factors on neurodevelopment and reduce the response of patients to antipsychotic agents. More recently, the role of Akt signaling in the functions of schizophrenia susceptibility genes such as disrupted-in-schizophrenia 1 (DISC-1), neuregulin-1 (NRG-1) and dysbindin-1 has been reported. Thus, Akt deficiency may create a context permissive for the expression of risk-gene effects in neuronal morphology and function. This paper reviews the role of Akt in the pathophysiology of schizophrenia and as a potential therapeutic strategy targeting Akt.
    Full-text · Article · Jul 2012 · Brain research
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