Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Geranylgeranyltransferase I inhibitors (GGTIs) represent a new class of anticancer drugs. However, the mechanism by which GGTIs inhibit tumor cell growth is still unclear. Here, we demonstrate that GGTI-298 and GGTI-2166 induce apoptosis in both cisplatin-sensitive and -resistant human ovarian epithelial cancer cells by inhibition of PI3K/AKT and survivin pathways. Following GGTI-298 or GGTI-2166 treatment, kinase levels of PI3K and AKT were decreased and survivin expression was significantly reduced. Ectopic expression of constitutively active AKT2 and/or survivin significantly rescue human cancer cells from GGTI-298-induced apoptosis. Previous studies have shown that Akt mediates growth factor-induced survivin, whereas p53 inhibits survivin expression. However, constitutively active AKT2 failed to rescue the GGTIs downregulation of survivin. Further, GGTIs suppress survivin expression and induce programmed cell death in both wild-type p53 and p53-deficient ovarian cancer cell lines. These data indicate that GGTI-298 and GGTI-2166 induce apoptosis by targeting PI3K/AKT and survivin parallel pathways independent of p53. Owing to the fact that upregulation of Akt and survivin as well as inactivation of p53 are frequently associated with chemoresistance, GGTIs could be valuable agents to overcome antitumor drug resistance.
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PMID:Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis. 1473 5

The phosphatidilinositol 3-kinase/protein kinase B (PI3K-AKT) pathway presents an exciting new target for molecular therapeutics. While exhibiting great promise, additional preclinical and clinical studies will be required to determine how best to target this pathway to improve patient outcome. A number of questions need to be answered prior to the implementation into patient care practices. As described below, the PI3K-AKT pathway regulates a broad spectrum of cellular processes, some of which are necessary to maintain normal physiological functions, which potentially contribute to the toxicity of the drugs targeting the pathway. Elucidation of the precise function of the PI3K-AKT isoforms, could promote the development of isoform specific approaches to provide a selective action on tumor cells. However, whether this will be possible due to conservation of structural domains is not yet clear. Inhibition of the PI3K-AKT pathway at multiple sites or a combination with inhibitors of different signaling pathways may allow the development of an acceptable therapeutic index for cancer management. Further, inhibition of the PI3K-AKT pathway combined with conventional chemotherapy or radiation therapy may provide a more effective strategy to improve patient outcome. As molecular therapeutics target the underlying defects in patient tumors, molecular diagnostics are required to identify patients with particular genetic aberrations in the pathway. It will be critical to provide adequate therapeutic strategies tailored to each patient. In addition, patients with different genetic backgrounds or in different health conditions could respond adversely to particular therapeutics. Therefore, identification of patients for particular drugs based on the underlying genetic defects in the tumor as well as the characteristics of the host would be of benefit for improving patient outcome. Linking the targeted therapeutics to molecular imaging approaches will determine appropriate biologically relevant dose for patients. It will also define expected tumor responsiveness and eventually will improve efficacy and decrease toxicity. In this regard, personalized molecular medicine is likely to soon provide effective cancer treatment.
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PMID:Targeting PI3K-AKT pathway for cancer therapy. 1476 63

Prolactin is an ancient hormone, with different functions in many species. The binding of prolactin to its receptor, a member of the cytokine receptor superfamily, results in the activation of different intracellular signaling pathways, such as JAK2/STAT5, MAP kinase, and PI3K/AKT. How prolactin elicits so many different biological responses remains unclear. Recently, microarray technology has been applied to identify prolactin target genes in different systems. Here, we attempt to summarize and compare the available data. Our comparison of the genes reported to be transcriptionally regulated by prolactin indicates that there are few genes in common between the different tissues. Among the organs studied, mammary and prostate glands displayed the largest number of overlaps in putative prolactin target genes. Some of the candidates have been implicated in tumorigenesis. The relevance and validation of microarray data, as well as comparison of the results obtained by different groups, will be discussed.
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PMID:Using gene expression arrays to elucidate transcriptional profiles underlying prolactin function. 1497 73

Nicotine is an important component in cigarette smoke that can activate the growth-promoting pathways to facilitate the development of lung cancer. However, the intracellular mechanism(s) by which nicotine promotes survival of lung cancer cells remains enigmatic. Bad is a proapoptotic BH3-only member of the Bcl2 family and is expressed in both small cell lung cancer and non-small cell lung cancer cells. Here we report that nicotine potently induces Bad phosphorylation at Ser112, Ser136, and Ser155 in a mechanism involving activation of MAPKs ERK1/2, PI3K/AKT, and PKA in human lung cancer cells. Nicotine-induced multi-site phosphorylation of Bad results in sequestering Bad from mitochondria and subsequently interacting with 14-3-3 in the cytosol. Treatment of cells with PKC inhibitor (staurosporine), MEK-specific inhibitor (PD98059), PI3 kinase inhibitor (LY294002), or PKA inhibitor (H89) blocks the nicotine-induced Bad phosphorylation that is associated with enhanced apoptotic cell death. The fact that beta-adrenergic receptor inhibitor (propranolol) blocks nicotine-induced activation of ERK1/2, AKT, PKA, Bad phosphorylation, and cell survival suggests that nicotine-induced Bad phosphorylation may occur through the upstream beta-adrenergic receptors. The fact that specific knockdown of Bad expression by RNA interference using short interfering RNA enhances cell survival and that nicotine has no additional survival effect on these cells suggests that Bad may act as a required target of nicotine. Thus, nicotine-induced survival may occur in a mechanism through multi-site phosphorylation of Bad, which may lead to development of human lung cancer and/or chemoresistance.
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PMID:Nicotine induces multi-site phosphorylation of Bad in association with suppression of apoptosis. 1503 18

To determine whether Insulin-like growth factor (IGF-I) treatment represents a potential means of enhancing the survival of cardiac muscle cells from adriamycin (ADR)-induced cell death, the present study examined the ability of IGF-I to prevent cell death. The study was performed utilising the embryonic, rat, cardiac muscle cell line, H9C2. Incubating cardiac muscle cells in the presence of adriamycin increased cell death, as determined by MTT assay and annexin V-positive cell number. The addition of 100 ng/mL IGF-I, in the presence of adriamycin, decreased apoptosis. The effect of IGF-I on phosphorylation of PI, a substrate of phosphatidylinositol 3-kinase (PI 3-kinase) or protein kinase B (AKT), was also examined in H9C2 cardiac muscle cells. IGF-I increased the phosphorylation of ERK 1 and 2 and PKC zeta kinase. The use of inhibitors of PI 3-kinase (LY 294002), in the cell death assay, demonstrated partial abrogation of the protective effect of IGF-I. The MEK1 inhibitor-PD098059 and the PKC inhibitor-chelerythrine exhibited no effect on IGF-1-induced cell protection. In the regulatory subunit of PI3K-p85- dominant, negative plasmid-transfected cells, the IGF-1-induced protective effect was reversed. This data demonstrates that IGF-I protects cardiac muscle cells from ADR-induced cell death. Although IGF-I activates several signaling pathways that contribute to its protective effect in other cell types, only activation of PI 3-kinase contributes to this effect in H9C2 cardiac muscle cells.
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PMID:Signal transduction of the protective effect of insulin like growth factor-1 on adriamycin-induced apoptosis in cardiac muscle cells. 1508 39

Skeletal muscle atrophy is a debilitating response to fasting, disuse, cancer, and other systemic diseases. In atrophying muscles, the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced, and this response is necessary for rapid atrophy. Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers. When Foxo activation is blocked by a dominant-negative construct in myotubes or by RNAi in mouse muscles in vivo, atrogin-1 induction during starvation and atrophy of myotubes induced by glucocorticoids are prevented. Thus, forkhead factor(s) play a critical role in the development of muscle atrophy, and inhibition of Foxo factors is an attractive approach to combat muscle wasting.
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PMID:Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. 1510 99

In healthy tissues, there is a balance between cell survival and death. This balance ensures epithelial cells survive in the right milieu, but undergo programmed cell death (apoptosis) when the environment is no longer supportive. Cells sense these changes primarily through receptors on the cell surface that bind to specific ligands present in the extracellular environment. These receptors, through signal transduction pathways, lead to promotion of cell survival or induction of cell death. One of the most important types of receptors regulating cell survival is the epidermal growth factor (EGF) receptors, while one of the most important types of receptors regulating apoptosis is the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors. EGF receptors activate survival signaling pathways including PI3K/AKT, Ras/MAPK, and JAK/STAT signaling pathways leading to cell survival. TRAIL activates apoptotic signaling pathways leading to caspase activation and mitochondrial dysfunction. The balance between these two signaling pathways determine whether a cell survives or dies. In disease states, this balance is altered. For example, epithelial-derived cancer cells often have increased expression of EGF receptors and are resistant to apoptosis. Understanding the interactions between survival and apoptotic signaling pathways mediated by EGF receptors and TRAIL death receptors will be essential to explain the role these pathways play in healthy and diseased cells.
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PMID:Epidermal growth factor and trail interactions in epithelial-derived cells. 1511 Jan 79

Radiation-induced endothelial cell apoptosis is involved in the development of many radiation injuries, including radiation-induced skin ulcers. The proangiogenic growth factors basic fibroblast growth factor (bFGF, NUDT6) and VEGF enhance endothelial cell survival. In the present study, we used primary cultured human umbilical vein endothelial cells (HUVECs) irradiated with (60)Co gamma rays to explore the effects of bFGF on radiation-induced apoptosis of HUVECs and its signaling pathways. We found that bFGF inhibited radiation-induced apoptosis of HUVECs, and that the effect was mediated by the PI3K/AKT pathway. This pathway was activated by exposure of irradiated HUVECs to bFGF, involving phosphorylation of FGFR, PI3K and AKT. The survival-enhancing effect of bFGF was abrogated by wortmannin and LY294002. Transfection of a dominant-negative mutant of AKT completely blocked the anti-apoptosis effect of bFGF in irradiated HUVECs. We also found evidence for the first time that bFGF induced BAD phosphorylation in the gamma-irradiated HUVECs. These results showed that the PI3K/AKT pathway participated in the bFGF-induced modulation of the survival of irradiated HUVECs. Activation of the PI3K/AKT pathway plays an important role in bFGF-induced endothelial cell survival in the treatment of radiation-induced skin ulcers.
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PMID:Basic fibroblast growth factor inhibits radiation-induced apoptosis of HUVECs. I. The PI3K/AKT pathway and induction of phosphorylation of BAD. 1516 50

AKT is a serine-threonine kinase involved in several different cellular functions, including the control of cell size and the regulation of survival and metabolism. Many studies have demonstrated that AKT also plays a critical role in the homeostasis of the cardiomyocyte. In these cells, AKT is activated by upstream molecules such as beta-adrenergic receptor, insulin-like growth factor-1 or insulin receptor, through PI3K alpha; whereas its activation is inhibited by the PTEN molecule. Downstream targets of AKT in the cardiomyocyte include glycogen-synthase kinase-3 beta and S6 kinase. Major effects of AKT activation in the cardiomyocyte are increase in cell size, prevention of apoptosis, and regulation of glucose metabolism. Interestingly, the AKT-dependent hypertrophic pathway is distinct from that activated by MAPKs. In fact, overexpression of AKT does not lead to MAPK activation. Our group has shown, moreover, that AKT exerts a positive effect on both inotropism and relaxation. In fact, mice overexpressing the E40K mutant of AKT in the heart showed improved cardiac function. Thus, AKT increases both cell size through the S6 kinase pathway and inotropism through the functional regulation of critical Ca(2+)-handling proteins. Therefore, AKT is a critical mediator of physiological hypertrophy.
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PMID:Regulation of cell size and contractile function by AKT in cardiomyocytes. 1520 Nov 65

Activation of the PI3K/AKT pathway may contribute to tumorigenesis. AKT mediates survival signals that protect cells from apoptosis and, thus, is a potentially important therapeutic target. To determine the frequency of AKT activation in human ovarian cancer, we screened a tumor tissue microarray with a phospho-specific pan-AKT (Ser473) antibody, which revealed elevated staining in 21 of 31 (68%) ovarian carcinomas. Phospho-AKT staining was associated with that of phospho (active)-mTOR in 27 of 31 (87%) ovarian tumors, with 17 (55%) tumors showing elevated phospho-mTOR positivity. We tested the effects of AKT/mTOR activation on the therapeutic sensitivity of ovarian cancer cells. Pretreatment of SKOV3 cells, which exhibit constitutive AKT activity under low serum conditions, with the PI3K inhibitor LY294002 augmented cisplatin-induced apoptosis. In contrast, ovarian cancer cell lines OVCAR4 and OVCAR5, which have low basal levels of AKT activity, did not show increased cisplatin-induced apoptosis when pretreated with LY294002. In addition, inhibition of mTOR activity with rapamycin resulted in G1 arrest in SKOV3 cells, but not in OVCAR4 or OVCAR5 cells. Collectively, these findings indicate that active AKT and downstream mTOR represent potentially important therapeutic and/or chemopreventive targets in ovarian cancer.
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PMID:AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. 1520 73


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