Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.2 (PDK1)
2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cadmium exposure increases the risk of prostate cancer. We now describe the effects of Cd2+ on signalling and proliferation in 1LN prostate cells. Cd2+ increased [3H]thymidine uptake and cell number twofold. Cd2+ elevated intracellular IP3, cytosolic-free Ca2+, phosphorylated MEK1/2, ERK1/2, p38 MAPK and JNK two- to threefold. Increased PDK1 and phosphorylation of the 85-kDa regulatory subunit of PI 3-kinase, Akt and p70s6k were also observed. Cd2+ treatment increased transcription factors NFkappaB and CREB, and the expression of c-fos and c-myc. Cd2+-induced increased uptake of [3H]thymidine was abolished by translational and transcriptional inhibitors, and Ca2+ channel blockers. Inhibition of phospholipase C and of Ca2+ binding to IP3 receptors inhibited Cd2+-induced DNA synthesis as did inhibition of tyrosine kinases, protein kinase C, PI 3-kinase, farnesyl transferase, MEK1/2, ERK1/2 and p38MAPK. Thus signalling events, which are triggered on exposure of 1LN cells to submicromolar concentrations of Cd2+, induce increased proliferation of these cells.
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PMID:Induction of mitogenic signalling in the 1LN prostate cell line on exposure to submicromolar concentrations of cadmium+. 1449 49

Previously it has been reported that caveolin-1 (cav-1) has antiapoptotic activities in prostate cancer cells and functions downstream of androgenic stimulation. In this study, we demonstrate that cav-1 overexpression significantly reduced thapsigargin (Tg)-stimulated apoptosis. Examination of the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling cascade revealed higher activities of PDK1 and Akt but not PI3-K in cav-1-stimulated cells compared to control cells. We subsequently found that cav-1 interacts with and inhibits serine/threonine protein phosphatases PP1 and PP2A through scaffolding domain binding site interactions. Deletion of the cav-1 scaffolding domain significantly reduces phosphorylated Akt and cell viability compared with wild-type cav-1. Analysis of potential substrates for PP1 and PP2A revealed that cav-1-mediated inhibition of PP1 and PP2A leads to increased PDK1, Akt, and ERK1/2 activities. We demonstrate that increased Akt activities are largely responsible for cav-1-mediated cell survival using dominant-negative Akt mutants and specific inhibitors to MEK1/MEK and show that cav-1 increases the half-life of phosphorylated PDK1 and Akt after inhibition of PI3-K by LY294002. We further demonstrate that cav-1-stimulated Akt activities lead to increased phosphorylation of multiple Akt substrates, including GSK3, FKHR, and MDM2. In addition, overexpression of cav-1 significantly increases translocation of phosphorylated androgen receptor to nucleus. Our studies therefore reveal a novel mechanism of Akt activation in prostate cancer and potentially other malignancies.
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PMID:Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A. 1464 48

The alpha2-macroglobulin signalling receptor is upregulated in highly metastatic 1-LN prostate cancer cells. Stimulation of 1-LN cells with activated alpha2-macroglobulin (alpha2M*) caused a two- to threefold increase in [3H]thymidine uptake and cell number. These events require the Ras-dependent MAPK and PI 3-kinase/Akt signalling cascades. Incubation of 1-LN cells with alpha2M* induced Grb2, shc, sos and Raf-1 expression, as well as phosphorylation of MEK 1/2, ERK 1/2, p38 MAPK and JNK. This treatment also increased PI 3-kinase activation, PDK1 expression, Akt phosphorylation and p70s6k phosphorylation. Levels of the early gene products c-fos protein and thymidylate synthase were comparably increased. Exposure of 1-LN cells to alpha2M* significantly raised the levels of phosphorylated CREB by about 15-20 min and phosphorylated p53 by about 60-90 min of incubation. We conclude that the growth regulatory effects of ligating the alpha2M* signalling receptor on 1-LN cells are exerted via the onset and crosstalk between the Ras-dependent MAPK and PI 3-kinase/Akt signalling cascades.
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PMID:Potentiation of signal transduction mitogenesis and cellular proliferation upon binding of receptor-recognized forms of alpha2-macroglobulin to 1-LN prostate cancer cells. 1470 37

The blockade of Akt activation through the inhibition of 3-phosphoinositide-dependent kinase-1 (PDK-1) represents a major signaling mechanism whereby celecoxib mediates apoptosis. Celecoxib, however, is a weak PDK-1 inhibitor (IC(50), 48 microM), requiring at least 30 microM to exhibit discernable effects on the growth of tumor cells in vitro. Here, we report the structure-based optimization of celecoxib to develop PDK-1 inhibitors with greater potency in enzyme inhibition and growth inhibition. Kinetics of PDK-1 inhibition by celecoxib with respect to ATP suggest that celecoxib derivatives inhibit PDK-1 by competing with ATP for binding, a mechanism reminiscent to that of many kinase inhibitors. Structure-activity analysis together with molecular modeling was used to generate compounds that were tested for their potency in inhibiting PDK-1 kinase activity and in inducing apoptosis in PC-3 prostate cancer cells. Docking of potent compounds into the ATP-binding site of PDK-1 was performed for lead optimization, leading to two compounds, OSU-03012 and OSU-03013, with IC(50) values in PDK-1 inhibition and apoptosis induction in the low microM range. Exposure of PC-3 cells to these agents led to Akt dephosphorylation and inhibition of p70 S6 kinase activity. Moreover, overexpression of constitutively active forms of PDK-1 and Akt partially protected OSU-03012-induced apoptosis. Screening in a panel of 60 cell lines and more extensive testing in PC-3 cells indicated that the mean concentration for total growth inhibition was approximately 3 microM for both agents. Considering the conserved role of PDK-1/Akt signaling in promoting tumorigenesis, these celecoxib analogs are of translational relevance for cancer prevention and therapy.
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PMID:From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors. 3093 80

We developed a high-throughput HTRF (homogeneous time-resolved fluorescence) assay for Akt kinase activity and screened approx. 270000 compounds for their ability to inhibit the three isoforms of Akt. Two Akt inhibitors were identified that exhibited isoenzyme specificity. The first compound (Akt-I-1) inhibited only Akt1 (IC50 4.6 microM) while the second compound (Akt-I-1,2) inhibited both Akt1 and Akt2 with IC50 values of 2.7 and 21 microM respectively. Neither compound inhibited Akt3 nor mutants lacking the PH (pleckstrin homology) domain at concentrations up to 250 microM. These compounds were reversible inhibitors, and exhibited a linear mixed-type inhibition against ATP and peptide substrate. In addition to inhibiting kinase activity of individual Akt isoforms, both inhibitors blocked the phosphorylation and activation of the corresponding Akt isoforms by PDK1 (phosphoinositide-dependent kinase 1). A model is proposed in which these inhibitors bind to a site formed only in the presence of the PH domain. Binding of the inhibitor is postulated to promote the formation of an inactive conformation. In support of this model, antibodies to the Akt PH domain or hinge region blocked the inhibition of Akt by Akt-I-1 and Akt-I-1,2. These inhibitors were found to be cell-active and to block phosphorylation of Akt at Thr308 and Ser473, reduce the levels of active Akt in cells, block the phosphorylation of known Akt substrates and promote TRAIL (tumour-necrosis-factor-related apoptosis-inducing ligand)-induced apoptosis in LNCap prostate cancer cells.
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PMID:Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors. 1545 5

Because of the unavailability of effective therapies to block or reverse the progression of androgen-independent prostate cancer, it seems obvious to target growth signaling pathways for which frequently recurring mutations have been identified. Acquired mutations of the PTEN gene have been reported in several tumor types, including up to 30% - 60% of prostate cancer tumors. This results in constitutive activation of the PI3K/Akt pathway which then represents a major target to prevent dysfunctions in cell growth, survival and motility. Our experience and, therefore, our own tools allow us to design new inhibitors of growth factor receptor tyrosine kinase, PDK-1 and farnesyltransferase activities. These original compounds could selectively switch off one or several steps of the multifunctional pathway and constitute lead compounds in the design of new classes of potent drugs.
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PMID:[Involvement of PI3K/Akt pathway in prostate cancer. Potential strategies for developing targeted therapies]. 1580 3

This review presents some therapeutic interventions actually considered in prostate cancer therapy to compensate constitutive activation of the PI3K/Akt signalling pathway induced, particularly, by mutations of PTEN gene. Special emphasis is placed on applicability of EGF-R tyrosine kinase, COX-2, PDK-1, mTOR and farnesyltransferase inhibitors.
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PMID:Involvement of PI3K/Akt pathway in prostate cancer--potential strategies for developing targeted therapies. 1637 58

AKT inhibitors are potentially promising drug candidates for the treatment of cancer. The inhibitory effects of a potent and selective AKT/BKB small molecule inhibitor, 9-chloro-2-methylellipticinium acetate (CMEP), on the activation of AKT, its antiproliferation and apoptosis-inducing effects in prostate cancer cell lines: DU-145, PC-3, LNCaP, and CL-1, an androgen-independent LNCaP variant, and CL-1 xenograft mouse model were assessed by Western blot analysis, kinase assay, cell survival assay, and apoptosis assay in this report. It has been observed that the expression levels of AKT1, AKT2, and AKT3 vary, but the levels of phospho-Ser473 AKT and phospho-Thr308 AKT are quite unique in these cancer cell lines, and that CL-1 cells have the highest basal levels of AKT activation among these cell lines. In PC-3 cells, CMEP has been found to inhibit only AKT activation at both normal and serum-starvation conditions, not to inhibit PI3K, PDK1, or MAPK. More importantly, it has been discovered that CMEP inhibits cell proliferation, and induces apoptosis in prostate cancer cells which have high-levels of AKT activation and lack PTEN or harbor PTEN mutation, such as CL-1, LNCaP, and PC-3; only shows a minimal activity in DU-145 cancer cells which do not have AKT activation. Furthermore, it has been demonstrated that CMEP treatment inhibits phospho-Ser473 AKT and phospho-p70S6K while stimulating TSC2 in the tumor tissue from CL-1-bearing mice. In conclusion, by specific blockade of the activation of AKT, CMEP preferentially inhibits growth and induces apoptosis in prostate cancer cells which have high-levels of AKT activation.
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PMID:Blockade of AKT activation in prostate cancer cells with a small molecule inhibitor, 9-chloro-2-methylellipticinium acetate (CMEP). 1695 Feb 8

Protein kinase C-related kinases are regulated by phosphatidylinositol-3-kinase and Rho family GTPases. The isoform PRK1 has been characterized in detail in prostate cancer, but not in other carcinomas. We analyzed our prior microarray data for PRK1 gene expression in 175 carcinomas and evaluated tissue microarrays for protein expression in 251 carcinomas and a comprehensive group of normal tissues. We also used immunoblotting to determine the levels and phosphoactivation status of PRK1, PRK2, and PDK1 in 12 ovarian serous carcinomas, SKOV3 cells, and 3 samples of normal ovarian surface epithelium (OSE). The highest average level of PRK1 messenger RNA was observed in ovarian serous carcinomas compared with all other carcinomas, including those of the prostate, bladder/ureter, breast, colon, stomach/esophagus, kidney, liver, pancreas, and lung (P = .05). By immunohistochemistry, PRK1 was observed in selected normal cells, including epithelium from the gynecologic tract and hematolymphoid elements. All serous ovarian and endometrial endometrioid adenocarcinomas and mesotheliomas were immunoreactive for PRK1. The findings in nonserous ovarian and most carcinomas from the prostate, breast, and pancreas were also positive but less consistently so. In comparison with OSE, the serous carcinomas typically had greater pPRK1/total PRK1 (P = .02) as well as greater pPDK/total PDK (P = .01). The relative phosphorylation status of these 2 kinases correlated within each sample. In summary, PRK1 is present in various malignancies, but especially in serous carcinomas, where the increased activation status of PRK1 and its upstream regulator, PDK, as compared with normal OSE suggests a role in ovarian cancer development or progression.
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PMID:PRK1 distribution in normal tissues and carcinomas: overexpression and activation in ovarian serous carcinoma. 1942 17

Loss of function at the Pten tumor-suppressor locus is a common genetic modification found in human prostate cancer. While recent in vivo and in vitro data support an important role of aberrant ErbB-2 signaling to clinically relevant prostate target genes, such as cyclin D1, the role of Pten in ErbB-2-induced prostate epithelial proliferation is not well understood. In the Pten-deficient prostate cancer cell line, LNCaP, restoration of Pten was able to inhibit ErbB-2- and heregulin-induced cell cycle progression, as well as cyclin D1 protein levels and promoter activity. Previously, we established that probasin-driven ErbB-2 transgenic mice presented with high-grade prostate intraepithelial neoplasia and increased nuclear cyclin D1 levels. We show that mono-allelic loss of pten in the probasin-driven-ErbB-2 model resulted in increased nuclear cyclin D1 and proliferating cell nuclear antigen levels and decreased disease latency compared to either individual genetic model and, unlike the probasin-driven-ErbB-2 mice, progression to adenocarcinoma. Activated 3-phosphoinositide-dependent protein kinase-1 was observed during cancer initiation combined with the activation of p70S6K (phospho-T389) and inactivation of the 4E-binding protein-1 (phosphorylated on T37/46) and was primarily restricted to those cases of prostate cancer that had progressed to adenocarcinoma. Activation of mTOR was not seen. Our data demonstrates that Pten functions downstream of ErbB-2 to restrict prostate epithelial transformation by blocking full activation of the PDK1 signaling cascade.
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PMID:A reduction in Pten tumor suppressor activity promotes ErbB-2-induced mouse prostate adenocarcinoma formation through the activation of signaling cascades downstream of PDK1. 1944 6


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