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#28652403   2017/06/27 Save this To Up

Protease-activated receptor-4 and purinergic receptor P2Y12 dimerize, co-internalize, and activate Akt signaling via endosomal recruitment of β-arrestin.

Vascular inflammation and thrombosis require the concerted actions of several different agonists, many of which act on G protein-coupled receptors (GPCRs). GPCR dimerization is a well-established phenomenon that can alter protomer function. In platelets and other cell types, protease-activated receptor-4 (PAR4) has been shown to dimerize with the purinergic receptor P2Y12 to coordinate β-arrestin-mediated Akt signaling, an important mediator of integrin activation. However, the mechanism by which the PAR4-P2Y12 dimer controls β-arrestin-dependent Akt signaling is not known. We now report that PAR4 and P2Y12 heterodimer internalization is required for β-arrestin recruitment to endosomes and Akt signaling. Using bioluminescence resonance energy transfer, immunofluorescence microscopy, and co-immunoprecipitation in cells expressing receptors exogenously and endogenously, we demonstrate that PAR4 and P2Y12 specifically interact and form dimers expressed at the cell surface. We also found that activation of PAR4 but not of P2Y12 drives internalization of the PAR4-P2Y12 heterodimer. Remarkably, activated PAR4 internalization was required for recruitment of β-arrestin to endocytic vesicles, which was dependent on co-expression of P2Y12. Interestingly, stimulation of the PAR4-P2Y12 heterodimer promotes β-arrestin and Akt co-localization to intracellular vesicles. Moreover, activated PAR4-P2Y12 internalization is required for sustained Akt activation. Thus, internalization of the PAR4-P2Y12 heterodimer is necessary for β-arrestin recruitment to endosomes and Akt signaling and lays the foundation for examining whether blockade of PAR4 internalization reduces integrin and platelet activation.

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#28634229   2017/06/21 Save this To Up

Akt activation by Ca(2+)/calmodulin-dependent protein kinase kinase 2 (CaMKK2) in ovarian cancer cells.

Hyperactivation of Akt is associated with oncogenic changes in the growth, survival, and chemoresistance of cancer cells. The PI3K/phosphoinositide-dependent kinase (PDK) 1 pathway represents the canonical mechanism for phosphorylation of Akt at its primary activation site, Thr-308. We observed that Ca(2+)/calmodulin (CaM)-dependent protein kinase kinase 2 (β) (CaMKK2) is highly expressed in high-grade serous ovarian cancer, and we investigated its role in Akt activation in ovarian cancer (OVCa) cell lines (OVCAR-3, SKOV-3, and Caov-3). Knockdown or pharmacological inhibition of CaMKK2 produced phenotypes expected of Akt inhibition, including reductions in cell growth and cell viability and in the regulation of Akt downstream targets involved in G1/S transition and apoptosis. CaMKK2 knockdown or inhibition decreased Akt phosphorylation at Thr-308 and Ser-473 to extents similar to those of PDK1 knockdown or PI3K inhibition. Combined CaMKK2 and PDK1 knockdown or CaMKK and PI3K inhibition, respectively, produced additive effects on p-Akt and cell growth, consistent with direct Akt phosphorylation by CaMKK2. This conclusion was supported by the absence of effects of CaMKK2 knockdown/inhibition on alternative means of activating Akt via p-Akt Thr-450, p-PDK1 Ser-241, or p-IRS1 Ser-636/639. Recombinant CaMKK2 directly activated recombinant Akt by phosphorylation at Thr-308 in a Ca(2+)/CaM-dependent manner. In OVCa cells, p-Akt Thr-308 was significantly inhibited by intracellular Ca(2+)i chelation or CaM inhibition. Ionomycin-induced Ca(2+) influx promoted p-Akt, an effect blocked by PDK1, and/or CaMKK2, siRNAs, and by PI3K and/or CaMKK inhibitors. CaMKK2 knockdown potentiated the effects of the chemotherapeutic drugs carboplatin and PX-866 to reduce proliferation and survival of OVCa cells.

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p130Cas-associated protei Aurora Kinase B Inhibitor Aurora Kinase B Inhibitor Recombinant Polyphosphate Ovarian cancer tissue arr High density ovarian canc Multiple ovarian cancer t Ovarian cancer test tissu to M-Calpain (E.C. 3.4.2 CA125, Ovarian Cancer An AKT1 (dn) Inducible Glycerol kinase

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#28581009   2017/06/05 Save this To Up

Decoding the anticancer activity of VO-clioquinol compound: the mechanism of action and cell death pathways in human osteosarcoma cells.

Vanadium compounds were studied in recent years by considering them as a representative of a new class of non-platinum metal anticancer drugs. However, a few challenges still remain in the discovery of new molecular targets of these new metallodrugs. Studies on cell signaling pathways related to vanadium compounds have scarcely been reported and so far this information is highly critical for identifying novel targets that play a key role in the antitumor actions of vanadium complexes. This research deals with the alterations in the intracellular signaling pathways promoted by an oxovanadium(iv) complex with the clioquinol (5-chloro-7-iodo-8-quinolinol), VO(CQ)2, on a human osteosarcoma cell line (MG-63). Herein are reported, for the first time, the antitumor properties of VO(CQ)2 and the relative abundance of 224 proteins (which are involved in most of the common intracellular pathways) to identify novel targets of the studied complex. Besides, full-length human recombinant AKT1 kinase was produced by using an IVTT system to evaluate the variation of relative tyrosin-phosphorylation levels caused by this compound. The results of the differential protein expression levels reveal several up-regulated proteins such as CASP3, CASP6, CASP7, CASP10, CASP11, Bcl-x, DAPK and down-regulated ones, such as PKB/AKT, DIABLO, among others. Moreover, cell signaling pathways involved in several altered pathways related to the PKC and AP2 family have been identified in both treatments (2.5 and 10 μM) suggesting the crucial antitumoral role of VO(CQ)2. Finally, it has been demonstrated that this compound (10 μM, 6 h) triggers a decrease of 2-fold in in situ AKT1 expression.

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#28522609   2017/05/19 Save this To Up

Coagulation factor VIIa-mediated protease-activated receptor 2 activation leads to β-catenin accumulation via the AKT/GSK3β pathway and contributes to breast cancer progression.

Cell migration and invasion are very characteristic features of cancer cells that promote metastasis, which is one of the most common causes of mortality among cancer patients. Emerging evidence has shown that coagulation factors can directly mediate cancer-associated complications either by enhancing thrombus formation or by initiating various signaling events leading to metastatic cancer progression. It is well established that, apart from its distinct role in blood coagulation, coagulation factor FVIIa enhances aggressive behaviors of breast cancer cells, but the underlying signaling mechanisms still remain elusive. To this end, we investigated FVIIa's role in the migration and invasiveness of the breast cancer cell line MDA-MB-231. Consistent with previous observations, we observed that FVIIa increased the migratory and invasive potential of these cells. We also provide molecular evidence that protease-activated receptor 2 activation followed by PI3K-AKT activation and GSK3β inactivation is involved in these processes and that β-catenin, a well known tumor-regulatory protein, contributes to this signaling pathway. The pivotal role of β-catenin was further indicated by the up-regulation of its downstream targets cyclin D1, c-Myc, COX-2, MMP-7, MMP-14, and Claudin-1. β-Catenin knockdown almost completely attenuated the FVIIa-induced enhancement of breast cancer migration and invasion. These findings provide a new perspective to counteract the invasive behavior of breast cancer, indicating that blocking PI3K-AKT pathway-dependent β-catenin accumulation may represent a potential therapeutic approach to control breast cancer.

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#28063486   2017/01/08 Save this To Up

A High-Throughput Fluorometric Assay for Lipid-Protein Binding.

An increasing number of intracellular and extracellular proteins are shown to interact with membrane lipids under physiological conditions. For rapid and robust quantitative measurement of lipid-protein interaction, we developed a sensitive fluorescence quenching-based assay that is universally applicable to all proteins and lipids. The assay employs fluorescence protein (FP)-tagged proteins whose fluorescence emission intensity is decreased when they bind vesicles containing quenching lipids. This simple assay can be performed with a fluorescence plate reader or a spectrofluorometer and optimized for different proteins with various combinations of FPs and quenching lipids. The assay allows a rapid, sensitive, and accurate determination of lipid specificity and affinity for various lipid-binding proteins, and high-throughput screening of molecules that modulate their membrane binding.

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#27748846   2016/10/17 Save this To Up

Sulfatase 2 facilitates lymphangiogenesis in breast cancer by regulating VEGF-D.

In our previous studies, sulfatase 2 (Sulf2) was found to upregulate vascular endothelial growth factor-D (VEGF-D) expression in breast cancer. As VEGF-D plays an important role in lymphangiogenesis, we hypothesized that Sulf2 facilitates lymphangiogenesis in breast cancer by regulating VEGF-D. To evaluate the functions of Sulf2 on lymphangiogenesis in breast cancer, proliferation, apoptosis, cell cycle, cell mobility and tube-formation of lymphatic endothelial cells (LECs) were measured in vitro. Lymphangiogenesis in nude mouse ears and breast cancer xenografts were examined in vivo. Furthermore, the expression levels of related signaling pathway genes were screened and verified in LECs. We found that Sulf2 significantly increased the mobility and tube formation of the LECs, inhibited cisplatin-induced LEC apoptosis, but had no effect on cell proliferation and the cell cycle. Moreover, recombinant Sulf2 (rSulf2) combined with VEGF-D further promoted the proliferation, cell cycle, mobility and tube-like structure formation in the LECs, and at the same time inhibited cisplatin-induced apoptosis especially in the late stage. Sulf2 also significantly increased the density of lymphatic vessels in mouse ears and breast cancer xenografts in vivo. AKT1 was also shown to be upregulated and activated by Sulf2. Our results confirmed that Sulf2 facilitated lymphangiogenesis in breast cancer cells by regulating VEGF-D and that the AKT1‑related signaling pathway was involved.

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#27574028   2016/09/16 Save this To Up

Let‑7 miRNAs sensitize breast cancer stem cells to radiation‑induced repression through inhibition of the cyclin D1/Akt1/Wnt1 signaling pathway.

The tumor-suppressive let-7 family of microRNAs (miRNAs) has been previously identified to induce cell apoptosis, proliferation‑inhibition and suppression of the self‑renewal capacities of cancer stem cells (CSCs). However, let‑7‑mediated sensitization of tumors to radiation treatment remains to be investigated fully in triple negative breast cancer (TNBC), of which the clinical treatment is challenging. The inhibitory effect of let‑7 miRNAs on the self‑renewal ability of CSCs from TNBC was investigated. It was identified that radiation inhibited the self‑renewal ability of TNBC stem cells by inhibiting cyclin D1 and protein kinase B (Akt1) phosphorylation. Let‑7d stimulates radiation‑induced tumor repression, exerting synergistic effects with radiotherapy on stem cell renewal. Through western blotting, immunofluorescence and a luciferase assay, it was identified that reduced cyclin D1/Akt1/wingless type MMTV integration site family member 1 (Wnt1) signaling activity accounts for the let‑7‑induced radiation sensitization. Let‑7 directly inhibits cyclin D1 expression, resulting in low phosphorylation of Akt1, which is critical for the let‑7‑induced inhibition of mammosphere numbers. The let‑7d‑induced Akt1 inhibition contributed to tumor repression, with similar results to those obtained with Akt inhibitors. Furthermore, it was identified that the inhibition of Wnt1 is critical for the functioning of let‑7d, and that addition of recombinant Wnt1 abolished the effects of let‑7d on sensitization to radiotherapy. Let‑7d is suggested to be a promising therapeutic agent in the treatment of TNBC by targeting CSCs and sensitizing tumors to radiotherapy via inhibition of cyclin D1/Akt1/Wnt1 signaling.

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#27175625   2016/08/10 Save this To Up

Deciphering the effect of an oxovanadium(iv) complex with the flavonoid chrysin (VOChrys) on intracellular cell signalling pathways in an osteosarcoma cell line.

Vanadium complexes were studied during recent years and considered as a representative of a new class of non-platinum metal antitumor agents in combination with their low toxicity. However, a few challenges still remain in the discovery of new molecular targets for these novel metal-based drugs. The study of cell signaling pathways related to vanadium drugs, which is highly critical for identifying specific targets that play an important role in the antitumor activity of vanadium compounds, is scarce. This research deals with the alterations in intracellular signaling pathways promoted by an oxovanadium(iv) complex with the flavonoid chrysin [VO(chrysin)2EtOH]2 (VOChrys) in a human osteosarcoma cell line (MG-63). Herein we report for the first time the effect of [VO(chrysin)2EtOH]2 on the relative abundance of 224 proteins, which are involved in the most common intracellular pathways. Besides, full-length human recombinant (FAK and AKT1) kinases are produced using an in situ IVTT system and then we have evaluated the variation of relative tyrosine-phosphorylation levels caused by the [VO(chrysin)2EtOH]2 compound. The results of the differential protein expression levels reveal that several proteins such as PKB/AKT, PAK, DAPK, Cdk 4, 6 and 7, FADD, AP2, NAK, and JNK, among others, were altered. Moreover, cell signaling pathways related to the PTK2B, FAK, PKC families suggests an important role associated with the antitumor activity of [VO(chrysin)2EtOH]2 was demonstrated. Finally, the effect of this compound on in situ expressed FAK and AKT1 is validated by determining the phosphorylation level, which decreased in the former and increased in the latter.

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#27050099   2016/04/13 Save this To Up

N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells.

MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention.

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#26996309   2016/04/13 Save this To Up

Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms.

Akt is frequently hyperactivated in human cancers and is targeted for cancer therapy. However, the physiological consequences of systemic Akt isoform inhibition were not fully explored. We showed that while combined Akt1 and Akt3 deletion in adult mice is tolerated, combined Akt1 and Akt2 deletion induced rapid mortality. Akt2(-/-) mice survived hepatic Akt1 deletion but all developed spontaneous hepatocellular carcinoma (HCC), which is associated with FoxO-dependent liver injury and inflammation. The gene expression signature of HCC-bearing livers is similar to aggressive human HCC. Consistently, neither Akt1(-/-) nor Akt2(-/-) mice are resistant to diethylnitrosamine-induced hepatocarcinogenesis, and Akt2(-/-) mice display a high incidence of lung metastasis. Thus, in contrast to other cancers, hepatic Akt inhibition induces liver injury that could promote HCC.

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