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)

AMN107 (Novartis Pharmaceuticals, Basel, Switzerland) has potent in vitro and in vivo activity against the unmutated and most common mutant forms of Bcr-Abl. Treatment with the histone deacetylase inhibitor LBH589 (Novartis) depletes Bcr-Abl levels. We determined the effects of AMN107 and/or LBH589 in Bcr-Abl-expressing human K562 and LAMA-84 cells, as well as in primary chronic myelogenous leukemia (CML) cells. AMN107 was more potent than imatinib mesylate (IM) in inhibiting Bcr-Abl tyrosine kinase (TK) activity and attenuating p-STAT5, p-AKT, Bcl-x(L), and c-Myc levels in K562 and LAMA-84 cells. Cotreatment with LBH589 and AMN107 exerted synergistic apoptotic effects with more attenuation of p-STAT5, p-ERK1/2, c-Myc, and Bcl-x(L) and increases in p27 and Bim levels. LBH589 attenuated Bcr-Abl levels and induced apoptosis of mouse pro-B BaF3 cells containing ectopic expression of Bcr-Abl or the IM-resistant, point-mutant Bcr-AblT315I and Bcr-AblE255K. Treatment with LBH589 also depleted Bcr-Abl levels and induced apoptosis of IM-resistant primary human CML cells, including those with expression of Bcr-AblT315I. As compared with either agent alone, cotreatment with AMN107 and LBH589 induced more loss of cell viability of primary IM-resistant CML cells. Thus, cotreatment with LBH589 and AMN107 is active against cultured or primary IM-resistant CML cells, including those with expression of Bcr-AblT315I.
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PMID:Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells. 1653 4

Cancer and vascular diseases remain the predominant causes of morbidity and mortality in industrialized countries worldwide. The course of atherosclerosis with initiation, progression, and complication parallels the three stages of carcinogenesis with induction, growth, and invasion of tissue and neoangiogenesis. Within this framework, the oncogene c-Myc and growth factors pathways are acquiring increasing importance. Insulin-like growth factor-1 (IGF-1) pathway emerges among them for its versatile pleiotropic actions. A number of genes that permit extensive communication between IGF-1-AKT, p53, and mammalian target of rapamycin (mTOR) pathways have been identified. In turn these pathways lead to p53 transcriptional program, the forkhead transcriptional programs, autophagy, and translational controls, which determine cell growth or arrest, cell survival or death. The increased understanding of the extensive communication and coordination between all these pathways may enable to targeting these events and to prevent neoplastic and vascular diseases. Great effort has been focused on the development of new agents designed to target various steps of c-Myc, Ras, and IGF cascade. However, what have we recently learned about their safety and effectiveness? Here, we review the very recent advances in the identification of novel inhibitors as well as antisense oligonuleotides (ASOs) and siRNA that are proving their usefulness in ongoing clinical trials both in terms of toxicity and specificity.
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PMID:Targeting c-Myc, Ras and IGF cascade to treat cancer and vascular disorders. 1692 Dec 63

We have shown that endogenous activation of type 5 metabotropic glutamate (mGlu5) receptors supports the maintenance of a pluripotent, undifferentiated state in D3 mouse embryonic stem cells cultured in the presence of leukaemia inhibitory factor (LIF). Here, we examined the interaction between LIF and mGlu5 receptors using as a read-out the immediate early gene, c-Myc. The selective mGlu5 receptor antagonist, 2-methyl-6-(phenylenthynyl)pyridine (MPEP; 1 mum), reduced the increase in c-Myc protein levels induced by LIF by enhancing c-Myc ubiquitination. A reduction in c-Myc levels was also observed following small interfering RNA-mediated mGlu5 receptor gene silencing. MPEP reduced glycogen synthase kinase-3beta phosphorylation on Ser9, but increased phosphorylation of the phosphatidylinositol-3-kinase (PI-3-K) substrate, AKT. In our hands, activated PI-3-K reduced the stability of c-Myc, because (i) the PI-3-K inhibitor, LY294002, prevented the reduction in c-Myc levels induced by MPEP; and (ii) over-expression of AKT promoted c-Myc ubiquitination. All effects of MPEP were mimicked by protein kinase C (PKC) inhibitors and reversed by the PKC activator, tetradecanoylphorbol-13-acetate. We conclude that endogenous activation of mGlu5 receptors sustains the increase in c-Myc induced by LIF in embryonic stem cells by inhibiting both glycogen synthase kinase-3beta and PI-3-K, both effects resulting from the activation of PKC.
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PMID:Endogenously activated mGlu5 metabotropic glutamate receptors sustain the increase in c-Myc expression induced by leukaemia inhibitory factor in cultured mouse embryonic stem cells. 1698 52

MAP17 is a non-glycosylated membrane-associated protein that has been shown to be over-expressed in human carcinomas, suggesting a possible role of this protein in tumorigenesis. However, very little is known about the molecular mechanism mediating the possible tumor promoting properties of MAP17. To analyze the effect of MAP17 on cell survival, we used Rat1 fibroblasts model where Myc over-expression promotes apoptosis in low serum conditions. In the present work, we report that over-expression of MAP17 protects Rat1a fibroblasts from Myc-induced apoptosis through reactive oxygen species (ROS)-mediated activation of the PI3K/AKT signaling pathway. MAP17-mediated survival was associated with absence of Bax translocation to the mitochondria and reduced caspase-3 activation. We show that a fraction of PTEN undergoes oxidation in MAP17-over-expressing cells. Furthermore, activation of AKT by MAP17 as measured by Thr308 phosphorylation was independent of PI3K activity. Importantly, modulation of ROS by antioxidant treatment prevented activation of AKT, restoring the level of apoptosis in serum-starved Rat1/c-Myc fibroblasts. Finally, over-expression of a dominant-negative mutant of AKT in MAP17-expressing clones makes them sensitive to serum depletion. Our data indicate that MAP17 protein activates AKT through ROS and this is determinant to confer resistance to Myc-induced apoptosis in the absence of serum.
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PMID:MAP17 inhibits Myc-induced apoptosis through PI3K/AKT pathway activation. 1767 38

Subjects with Type II diabetes mellitus are more vulnerable in developing colorectal tumors, suggesting that hyperinsulinemia may stimulate proto-oncogene expression, and the existence of crosstalk between insulin signaling and pathways that are involved in colorectal tumor formation. We show here that insulin stimulates cell proliferation and c-Myc expression in colon cancer cell lines HT29 and Caco-2, intestinal non-cancer cell line IEC-6, and primary fetal rat intestinal cell (FRIC) cultures. The effect of insulin was blocked by phosphoinositide-3 Kinase (PI3K) inhibition, but only partially attenuated by inhibition of Protein kinase B (PKB), indicating the existence of both PKB-dependent and -independent mechanisms. The PKB-dependent mechanism of insulin-stimulated c-Myc expression in HT29 cells was shown to involve the activation of mTOR in c-Myc translation. In the investigation of the PKB-independent mechanism, we found that insulin-induced nuclear translocation of beta-catenin (beta-cat), an effector of Wnt signaling. Furthermore, insulin stimulated the expression of TopFlash, a Wnt-responsive reporter gene. Finally, chromatin immunoprecipitation (ChIP) detected significant increases in the binding of beta-cat to two TCF binding sites of the human c-Myc promoter following insulin treatment. Our observations support the existence of crosstalk between insulin and Wnt signaling pathways, and suggest that the crosstalk involves a PKB-independent mechanism.
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PMID:Both Wnt and mTOR signaling pathways are involved in insulin-stimulated proto-oncogene expression in intestinal cells. 1799 59

While small molecule inhibitors of the phosphatidylinositide-3-kinase (PI3K) are expected to impact the development of new cancer therapy, the tumor types and underlying cellular pathways determining inhibitor response remain poorly defined. In this report, we have studied anti-proliferative effects of the PI3K inhibitors WAY-266176 and WAY-266175 in a panel of histologically diverse cancer cells. Inactivation of PI3K caused potent growth suppression in some cells (MDA468, BT549, MDA361, MCF7, LNCap, PC3MM2) but minimal suppression in others (MDA231, MDA435, DU145, HCT116, A549), which correlated with a differential down-regulation of cyclin D1, c-Myc, and induction of apoptosis. A heightened PI3K/AKT/mTOR signaling was linked to the sensitive phenotype but did not generally predict inhibitor response. Interestingly, the resistant cells all displayed an elevated phospho-ERK that remained elevated after serum deprivation. In HCT116 cells, activation mutations in the PI3K catalytic subunit PIK3CA and Ki-Ras correlated with a resistant phenotype, which was partially sensitized by homologous replacement with the wild-type Ki-Ras but not by deletion of cellular PTEN. Depletion of Mek1 via siRNA in resistant cells enhanced PI3K inhibitor-induced growth suppression. Moreover, a profoundly augmented growth suppression and apoptosis were achieved in resistant cells by combination treatment with WAY-266176/WAY-266175 and Mek1 kinase inhibitor CI-1040 or UO126. The combination therapy efficiently inhibited mitogenic signaling and reduced expression of cyclin D1 and c-Myc. Our results identify deregulation of the Ras/Raf/Mek/ERK pathway as a dominant determinant in cancer cell resistance to PI3K inhibitors and highlight combined targeting of PI3K and Mek1 as an effective anticancer strategy.
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PMID:Response and determinants of cancer cell susceptibility to PI3K inhibitors: combined targeting of PI3K and Mek1 as an effective anticancer strategy. 1834 31

Despite promising results from clinical studies of ABL kinase inhibitors, a challenging problem that remains is the T315I mutation against which neither nilotinib nor dasatinib show significant activity. In the present study, we investigated the activity of a novel Aurora kinase inhibitor, VE-465, against leukemia cells expressing wild-type BCR-ABL or the T315I mutant form of BCR-ABL. We observed a dose-dependent reduction in the level of BCR-ABL autophosphorylation in VE-465-treated cells. Exposure to the combination of VE-465 and imatinib exerted an enhanced apoptotic effect in K562 cells. Combined treatment with VE-465 and imatinib caused more attenuation of the levels of phospho-AKT and c-Myc in K562 cells. Further, the isobologram indicated the synergistic effect of simultaneous exposure to VE-465 and imatinib in K562 cells. To assess the in vivo efficacy of VE-465, athymic nude mice were injected intravenously with BaF3 cells expressing wild-type BCR-ABL or the T315I mutant form. The vehicle-treated mice died of a condition resembling acute leukemia by 28 days; however, nearly all mice treated with VE-465 (75 mg/kg, twice daily; intraperitoneally for 14 days) survived for more than 56 days. Histopathological analysis of vehicle-treated mice revealed infiltration of the spleen. In contrast, histopathological analysis of organs from VE-465-treated mice demonstrated normal tissue architecture. Taken together, the present study shows that VE-465 exhibits a desirable therapeutic index that can reduce the in vivo growth of T315I mutant form and wild-type BCR-ABL-expressing cells in an efficacious manner.
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PMID:Activity of a novel Aurora kinase inhibitor against the T315I mutant form of BCR-ABL: in vitro and in vivo studies. 1842 56

The persistence of human T-cell leukemia/lymphoma virus-I (HTLV-I)-infected cells is dependent upon clonal expansion and up-regulation of telomerase (hTERT). We have previously found that in interleukin (IL)-2-independent transformed HTLV-I cells, Tax strongly activates the hTERT promoter through nuclear factor-kappaB (NF-kappaB)-mediated Sp1 and c-Myc activation. In IL-2-dependent cells and adult T-cell leukemia/lymphoma (ATLL) patient samples, however, Tax expression is very low to undetectable, yet these cells retain strong telomerase activity. This suggests the existence of compensatory mechanisms in IL-2-dependent cells and ATLL patients. In this study, we demonstrate that telomerase activity is significantly decreased upon IL-2 withdrawal in immortalized HTLV-I cell lines. Inhibition of PI3K or AKT signaling pathways reduced telomerase activity in HTLV-I cells. We found that IL-2/IL-2R signaling was associated with a PI3K-dependent/AKT-independent transcriptional up-regulation of the endogenous hTERT promoter. We found that activation of the PI3K pathway mediated cytoplasmic retention of the Wilms tumor (WTI) protein, which strongly suppressed the hTERT promoter. The importance of this regulatory pathway for telomerase expression is underscored by findings that the PI3K pathway is commonly found activated in cancer cells.
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PMID:Central role of PI3K in transcriptional activation of hTERT in HTLV-I-infected cells. 1880 72

c-MYC inhibits differentiation and regulates the process by which cells acquire biomass, cell growth. Down-regulation of c-MYC, reduced cell growth, and decreased activity of the PI3K/AKT/mTORC1 signal transduction pathway are features of the terminal differentiation of committed myeloid precursors to polymorphonuclear neutrophils. Since mTORC1 regulates growth, we hypothesized that pharmacological inhibition of mTORC1 by rapamycin may reverse the phenotypic effects of c-MYC. Here we show that granulocytes blocked in their ability to differentiate by enforced expression of c-MYC can be induced to differentiate by reducing exogenous c-MYC expression through rapamycin treatment. Rapamycin also reduced expression of endogenous c-MYC and resulted in enhanced retinoid-induced differentiation. Total cellular c-Myc mRNA and c-MYC protein stability were unchanged by rapamycin, however the amount of c-Myc mRNA associated with polysomes was reduced. Therefore rapamycin limited expression of c-MYC by inhibiting c-Myc mRNA translation. These findings suggest that mTORC1 could be targeted to promote terminal differentiation in myeloid malignancies characterized by dysregulated expression of c-MYC.
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PMID:Translational control of c-MYC by rapamycin promotes terminal myeloid differentiation. 1862 30

Although several mechanisms have been proposed to explain the putative role of beta-carotene in cancer, no studies have investigated a possible influence of beta-carotene on caveolin-1 (cav-1) pathway, an important intracellular signaling deregulated in cancer. Here, different human colon and prostate cancer cell lines, expressing (HCT-116, PC-3 cells) or not (Caco-2, LNCaP cells) cav-1, were treated with varying concentrations of beta-carotene (0.5-30 muM) for different periods of time (3-72 h) and the effects on cell growth were investigated. The results of this study show that (i) beta-carotene acted as a growth-inhibitory agent in cav-1-positive cells, but not in cav-1-negative cells; (ii) in cav-1-positive cells, the carotenoid downregulated in a dose- and time-dependent manner the expression of cav-1 protein and messenger RNA levels and inhibited AKT phosphorylation which, in turn, stimulated apoptosis by increasing the expression of beta-catenin and c-myc and the activity of caspases-3, -7, -8 and -9; when the carotenoid was removed from culture medium, a progressive increase in cell growth was observed with respect to beta-carotene-treated cells and (iii) the transfection of cav-1 in cav-1-negative cells increased cell sensitivity to beta-carotene by inducing apoptosis. This effect was accompanied by a reduction of both cav-1 and AKT phosphorylation and by an increase of c-myc and beta-catenin expression. Silencing of c-Myc attenuated beta-carotene-induced apoptosis and beta-catenin expression. All together, these data suggest that the modulation of cav-1 pathway by beta-carotene could be a novel mechanism by which the carotenoid acts as a potent growth-inhibitory agent in cancer cells.
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PMID:The sensitivity to beta-carotene growth-inhibitory and proapoptotic effects is regulated by caveolin-1 expression in human colon and prostate cancer cells. 1863 24


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