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)

Antitumour activity of docetaxel (Taxotere) in hormone-dependent (HD) and hormone-independent (HID) prostate cancer PAC120 xenograft model was previously reported, and its level was associated with HER2 protein expression. In the present study, we evaluate the antitumour effects of docetaxel combined with trastuzumab (Herceptin), an anti-HER2 antibody. Although trastuzumab alone had no effect on tumour growth, it potentiated the antitumour activity of docetaxel in HD tumours and more strongly in HID variants. Using the HID28 variant, we show that docetaxel treatment of tumour-bearing mice induces an increased HER2 mRNA expression of the tyrosine kinase receptor of 25-fold 24 h after docetaxel treatment, while HER2 protein and p-AKT decreased. This was followed by an increase of HER2 protein 3 days (two-fold) after docetaxel treatment and by a strong HER2 release in the serum of treated mice; expression of phospho-ERK, p27, BCL2 and HSP70 concomitantly increased. Similar molecular alterations were induced by docetaxel plus trastuzumab combination, except for that there was a transient and complete disappearance of AR and HSP90 proteins 24 h after treatment. We show that in addition to its known effects on tubulin and mitotic spindles, docetaxel induces complex signalisation pathway mechanisms in surviving cells, including HER2, which can be pharmacologically targeted. This study suggests that the docetaxel/trastuzumab combination may prove an effective therapeutic approach for HER2-expressing hormone-refractory prostate cancer.
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PMID:Potentiation of antitumour activity of docetaxel by combination with trastuzumab in a human prostate cancer xenograft model and underlying mechanisms. 1721 67

We characterized the effects of the small molecule epidermal growth factor receptor (EGFR) inhibitor gefitinib (ZD1839, Iressa) on cell proliferation in a panel of 17 human bladder cancer cell lines. Gefitinib inhibited DNA synthesis in a concentration-dependent fashion in 6 of 17 lines. Growth inhibition was associated with p27(Kip1) accumulation and decreased cyclin-dependent kinase 2 activity. Gefitinib also inhibited baseline EGFR, AKT, and extracellular signal-regulated kinase (ERK) phosphorylation in the EGFR-dependent cells maintained in serum-free medium, whereas it had no effect on baseline EGFR or ERK phosphorylation in the EGFR-independent cells. Analyses of candidate markers of EGFR dependency revealed that the gefitinib-sensitive cells expressed higher surface EGFR levels than the gefitinib-resistant lines. Gefitinib-sensitive cells generally expressed higher levels of E-cadherin and lower levels of vimentin than the gefitinib-resistant cells, but these correlations were not perfect, suggesting that these markers of epithelial-mesenchymal transition cannot be used by themselves to prospectively predict EGFR-dependent growth. Together, our results show that bladder cancer cells are markedly heterogeneous with respect to their sensitivity to EGFR antagonists. Although surface EGFR levels and epithelial-mesenchymal transition status seem to roughly correlate with responsiveness, they cannot be used by themselves to identify bladder tumors that will be sensitive to EGFR-directed therapy. However, comparing levels of p27(Kip1) or DNA synthesis before and after gefitinib exposure does identify the drug-sensitive cells.
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PMID:Molecular correlates of gefitinib responsiveness in human bladder cancer cells. 1723 87

PAX3 or PAX3-FKHR expression is implicated in cell transformation and tumourigenesis. Here, C2C12 myoblasts were transfected with a sense Pax3 vector and a pTet-On system to induce Pax3 expression, whereas to downregulate PAX3-FKHR, Rh18 was transfected with an antisense Pax3 with a pTet-On system. The inhibition of PAX3-FKHR in Rh18 induced upregulation of PTEN. Decreased resistance to apoptosis and increased transformation ability were observed in the Rh18 cells with PAX3-FKHR downregulation. Conversely, Pax3 induction in C2C12 cells downregulated the expression of PTEN and p27(Kip1). These results indicate that the involvement of PAX3 and PAX3-FKHR in rhabdomyosarcoma tumourigenesis may be through downregulation of PTEN tumour suppressor gene, affecting the PTEN/AKT survival pathway.
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PMID:PAX3 and PAX3-FKHR promote rhabdomyosarcoma cell survival through downregulation of PTEN. 1735 Jan 64

Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B-signaling pathway has been associated with multiple human cancers, including thyroid cancer. Recently, we showed that, similar to human thyroid cancer, the PI3K-AKT pathway is overactivated in both the thyroid and metastatic lesions of a mouse model of follicular thyroid carcinoma (TRbeta(PV/PV) mice). This TRbeta(PV/PV) mouse harbors a knockin mutant thyroid hormone receptor beta gene (TRbetaPV mutant) that spontaneously develops thyroid cancer and distant metastasis similar to human follicular thyroid cancer. That the activation of the PI3K-AKT signaling contributes to thyroid carcinogenesis raised the possibility that this pathway could be a potential therapeutic target in follicular thyroid carcinoma. The present study tested this possibility by treating TRbeta(PV/PV) mice with LY294002 (LY), a potent and specific PI3K inhibitor, and evaluating the effect of LY on the spontaneous development of thyroid cancer. LY treatment inhibited the AKT-mammalian target of rapamycin (mTOR)-p70(S6K) signaling, and it decreased cyclin D1 and increased p27(Kip1) expression to inhibit thyroid tumor growth and reduce tumor cell proliferation. LY treatment increased caspase 3 and decreased phosphorylated-BAD to induce apoptosis. In addition, LY treatment reduced the AKT-matrix metalloproteinase 2 signaling to decrease cell motility to block metastatic spread of thyroid tumors. Thus, these altered signaling pathways converged effectively to prolong survival of TRbeta(PV/PV) mice treated with LY. No significant adverse effects were observed for wild-type mice treated similarly with LY. The present study provides the first preclinical evidence for the in vivo efficacy for LY in the treatment of follicular thyroid cancer.
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PMID:Inhibition of phosphatidylinositol 3-kinase delays tumor progression and blocks metastatic spread in a mouse model of thyroid cancer. 1766 May 7

Jab1 is a co-activator of activating protein-1 (AP-1) transcription factor and the fifth subunit of the constitutive photomorphogenesis 9 (COP9) signalosome, which has been shown to mediate nuclear exportation and ubiquitin-dependent degradation of the tumor suppressor p27(Kip1). Jab1 is overexpressed in several types of human cancer. However, de-regulation of Jab1 gene expression in cancer cells is largely unclear. In this study, we reported that expression of Jab1 was stimulated by HER-2/neu oncogene via transcriptional activation. Promoter deletion and mutation analysis indicated that HER-2/neu stimulated Jab1 via the T cell factor (TCF) binding site located at the -380/-368 region of the human Jab1 promoter. DNA affinity precipitation assay and chromatin immunoprecipitation assay verified that binding of beta-catenin and TCF-4 to this consensus site was increased by HER-2/neu. In addition, dominant-negative mutant of TCF significantly attenuated the stimulatory effect of HER-2/neu. We also demonstrated that HER-2/neu increased beta-catenin/TCF-mediated Jab1 expression via the AKT signaling pathway because chemical inhibitor or dominant-negative mutant of AKT effectively attenuated the stimulatory action of HER-2/neu. IGF-I, which is a well-known AKT activator, also up-regulated the expression of Jab1 in NIH/3T3 and MCF-7 cells. Knockdown of Jab1 by small interfering RNA (siRNA) preferentially inhibited proliferation of HER-2/neu-overexpressing breast cancer cells. Taken together, our results suggest that HER-2/neu transcriptionally activates Jab1 expression to promote proliferation of breast cancer cells.
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PMID:HER-2/neu transcriptionally activates Jab1 expression via the AKT/beta-catenin pathway in breast cancer cells. 1791 96

Small molecule tyrosine kinase inhibitors, such as imatinib, are effective therapies for BCR-ABL-mediated human leukemias. However, clinical drug resistance occurs, which warrants development of alternative and/or complementary therapeutic strategies to target critical downstream signaling molecules. We recently demonstrated that disrupting 14-3-3/ligand association by a peptide-based 14-3-3 competitive antagonist R18 induces significant apoptosis, partially through reactivation of AKT-inhibited proapoptotic FOXO3a, in FGFR1 fusion-transformed hematopoietic cells. Here, we report that targeting 14-3-3 by R18 effectively induced significant apoptosis in Ba/F3 and K562 cells expressing BCR-ABL, similarly through liberation and reactivation of FOXO3a. Moreover, R18 sensitized BCR-ABL-transformed cells to inhibition with MEK1 inhibitor U0126, Bcl-2 inhibitor GX15-070, or mTOR inhibitor rapamycin. Treatment with these reagents potentiated R18-induced reactivation of proapoptotic FOXO3a with enhanced expression of downstream transcription targets p27(kip1) and Bim1. Furthermore, R18-induced apoptotic cell death in cells expressing diverse imatinib-resistant BCR-ABL mutants, including T315I. This inhibition was enhanced by R18 in combination with U0126 and rapamycin. Thus, our findings suggest that targeting 14-3-3 may potentiate the effects of conventional therapy for BCR-ABL-associated hematopoietic malignancies, and overcome drug resistance.
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PMID:Targeting 14-3-3 sensitizes native and mutant BCR-ABL to inhibition with U0126, rapamycin and Bcl-2 inhibitor GX15-070. 1807 35

Previous studies in animal models have shown enhanced efficacy of a combined treatment of statins and Nonsteroidal anti-inflammatory drugs against colorectal cancer development. In our study, we investigated the combinational effects of atorvastatin and celecoxib in 2 human colon cancer cell lines HCT116 and HT29. Celecoxib moderately inhibited the growth of both cell lines with a similar IC(50) of 40-50 microM, whereas atorvastatin showed stronger growth inhibitory effect in HCT116 cells than in HT29 cells (IC(50) of 5-8 microM vs. 30-35 microM) after treatment for 48-72 hr. The combination of these 2 agents produced strong synergistic actions, as determined by isobologram analysis. Flow cytometry analysis indicated that the combination treatment for 24 hr caused extensive cell cycle arrest in G0/G1 phase; whereas at 48 hr or longer, apoptosis was induced significantly. The effects produced by the combination were much stronger than that by atorvastatin or celecoxib alone. Our results further demonstrated that the combinational effects of atorvastatin/celecoxib were associated with increased levels of p21(Cip1/Waf1), p27(Kip1), and phospho-JNK; decreased levels of phospho-AKT and hyper-phosphorylated Rb; and activation of caspase cascade. Atorvastatin/celecoxib combination also selectively modified membrane localization of small G-proteins, such as RhoA, RhoB and RhoC, which may contribute to the anti-cancer effects. Taken together, the results demonstrated a strong synergy between the actions of atorvastatin and celecoxib in growth inhibition and killing of human colon cancer cells. The present work suggests the possible therapeutic application of this combination and provides leads for mechanistic and biomarker investigations in clinical trials.
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PMID:Combination of atorvastatin and celecoxib synergistically induces cell cycle arrest and apoptosis in colon cancer cells. 1849 99

Cardiomyocytes actively proliferate during embryogenesis and withdraw from the cell cycle during neonatal stages. FOXO (Forkhead O) transcription factors are a direct target of phosphatidylinositol-3 kinase/AKT signaling in skeletal and smooth muscle and regulate expression of the Cip/Kip family of cyclin kinase inhibitors in other cell types; however, the interaction of phosphatidylinositol-3 kinase/AKT signaling, FOXO transcription factors, and cyclin kinase inhibitor expression has not been reported for the developing heart. Here, we show that FOXO1 and FOXO3 are expressed in the developing myocardium concomitant with increased cyclin kinase inhibitor expression from embryonic to neonatal stages. Cell culture studies show that embryonic cardiomyocytes are responsive to insulin-like growth factor 1 stimulation, which results in the induction of the phosphatidylinositol-3 kinase/AKT pathway, cytoplasmic localization of FOXO proteins, and increased myocyte proliferation. Likewise, adenoviral-mediated expression of AKT promotes cardiomyocyte proliferation and cytoplasmic localization of FOXO. In contrast, increased expression of FOXO1 negatively affects myocyte proliferation. In vivo myocyte-specific transgenic expression of FOXO1 during heart development causes embryonic lethality at embryonic day 10.5 because of severe myocardial defects that coincide with premature activation of p21(cip1), p27(kip1), and p57(kip2) and decreased myocyte proliferation. Transgenic expression of dominant negative FOXO1 in cardiomyocytes does not obviously affect heart development at embryonic day 10.5, but results in abnormal morphology of the myocardium by embryonic day 18.5 along with decreased cyclin kinase inhibitor expression and increased myocyte proliferation. These data support FOXO transcription factors as negative regulators of cardiomyocyte proliferation and promoters of neonatal cell cycle withdrawal during heart development.
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PMID:Regulation of cardiomyocyte proliferation and myocardial growth during development by FOXO transcription factors. 1821 83

PTEN is a tumor suppressor gene but whether cancer can develop in all PTEN-deficient cells is not known. In T cell-specific PTEN-deficient (tPTEN-/-) mice, which suffer from mature T cell lymphomas, we found that premalignancy, as defined by elevated AKT and senescence pathways, starts in immature T cell precursors and surprisingly not in mature T cells. Premalignancy only starts in 6-week-old mice and becomes much stronger in 9-week-old mice although PTEN is lost since birth. tPTEN-/- immature T cells do not become tumors, and senescence has no role in this model because these cells exist in a novel cell cycle state, expressing proliferating proteins but not proliferating to any significant degree. Instead, the levels of p27(kip1), which is lower in tPTEN-/- immature T cells and almost nonexistent in tPTEN-/- mature T cells, correlate with the proliferation capability of these cells. Interestingly, transient reduction of these cancer precursor cells in adult tPTEN-/- mice within a crucial time window significantly delayed lymphomas and mouse lethality. Thus, loss of PTEN alone is not sufficient for cells to become cancerous, therefore other developmental events are necessary for tumor formation.
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PMID:Normal development is an integral part of tumorigenesis in T cell-specific PTEN-deficient mice. 1825 Mar 1

Androgen plays an important role in the growth of prostate cancer, but the molecular mechanism that underlies the development of resistance to anti-androgen therapy remains unknown. In this paper, we review the role of cell cycle regulators and steroid receptor co-activators for prostate cancer growth and survival. Cyclin E has been shown to increase the transactivation activity of the human androgen receptor and the proliferation of prostate cancer cells. On the other hand, p27 using an adenovirus vector was shown to reduce the size of tumors of human prostate cancer xenografts. Steroid receptor coactivator-3 (SRC-3) is often over-expressed in prostate cancers. Our results indicate that overexpression of SRC-3 can modulate the AKT (protein kinase B) signaling pathway and stimulate cell growth in prostate cancer. In contrast, down-regulation of SRC-3 expression by small interfering RNA suppresses cell growth.
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PMID:[Molecular targeted therapy for prostate cancer]. 1826 Mar 63


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