Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt

Costa, Barbara; Dangate, Milind Shrinivas; Vetro, M.; Donvito, Giulia; Gabrielli, Luca; Amigoni, Loredana; Cassinelli, Giuliana; Lanzi, Cinzia; Ceriani, Michela; Gioia, Luca De; Filippi, Giulia; Cipolla, Laura; Zaffaroni, Nadia; Perego, Paola; Colombo, Diego

doi:10.1016/j.bmc.2016.05.031

Cited by 10 publications

(7 citation statements)

References 43 publications

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“…As one of the most important tumor-related signaling pathways, the activation of AKT/GSK-3β/β-catenin signaling pathway played a pivotal role in the development of tumors. Akt was a serine/threonine protein kinase that played an important role in cell proliferation, differentiation, inhibition and apoptosis [26, 27]. In the AKT/GSK-3β/β-catenin signaling pathway, GSK-3β acts as a key gene in phosphorylation and degradation of β-catenin [28].…”

Section: Discussionmentioning

confidence: 99%

miR-96 exerts carcinogenic effect by activating AKT/GSK-3β/β-catenin signaling pathway through targeting inhibition of FOXO1 in hepatocellular carcinoma

et al. 2019

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Background The aim of this research was to investigate the mechanism of miR-96 affecting hepatocellular carcinoma (HCC). Methods mRNA and protein expression was detected by qRT-PCR and Western blot, respectively. HepG2 cells were transfected and grouped as follows: miR-NC group, miR-mimics group, NC + Vector group, mimics + Vector group, mimics + FOXO1 group. Luciferase reporter assay was performed. MTT and Transwell assay was conducted. In vivo studies by nude mice were performed. Immunohistochemistry and immunofluorescence was executed. Results Up-regulated miR-96 and down-regulated FOXO1 was found in tumor tissues and HepG2 cells ( P < 0.01). FOXO1 was directly suppressed by miR-96. Compared with NC + Vector group, mimics + Vector group has higher OD495 value ( P < 0.05), higher migration and invasion cells ( P < 0.01), larger transplanted tumor volume ( P < 0.01), lower FOXO1 positive cell numbers ( P < 0.01), higher p-AKT and p-GSK-3β expression ( P < 0.01), lower p-β-catenin expression ( P < 0.01), more β-catenin expression in the nucleus ( P < 0.01). Compared with mimics + Vector group, mimics + FOXO1 group has lower OD495 value ( P < 0.05), lower migration and invasion cells (P < 0.01), smaller transplanted tumor volume ( P < 0.01), higher FOXO1 positive cells ( P < 0.01), lower p-AKT and p-GSK-3β expression ( P < 0.01), higher p-β-catenin expression ( P < 0.01), less β-catenin expression in the nucleus ( P < 0.01). Conclusion miR-96 exerts carcinogenic effect by activating AKT/GSK-3β/β-catenin signaling pathway through targeting inhibition of FOXO1 in HCC.

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Section: Discussionmentioning

confidence: 99%

miR-96 exerts carcinogenic effect by activating AKT/GSK-3β/β-catenin signaling pathway through targeting inhibition of FOXO1 in hepatocellular carcinoma

et al. 2019

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“…Human CCL28 is a natural ligand-agonist for human CCR10 9 . A6730 produces a conformational change in Akt that prevents it from associating with upstream kinases, thereby abrogating Akt phosphorylation 10 .…”

Section: Methodsmentioning

confidence: 99%

The chemokine receptor CCR10 promotes inflammation-driven hepatocarcinogenesis via PI3K/Akt pathway activation

Chen

et al. 2018

Cell Death Dis

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G-protein-coupled receptor (GPCR)-related proteins are dysregulated and the GPCR CC-chemokine receptor 10 (CCR10) is significantly upregulated in inflammation-driven HCC. However, CCR10′s role in inflammation-driven hepatocarcinogenesis remains unknown. The aim of this study was to evaluate the role of CCR10 in inflammation-driven hepatocarcinogenesis. Via a targeted gene expression microarray screening alterations in GPCR family gene expression, we found CCR10 to be significantly upregulated in hepatocytes isolated from inflammation-driven human HCC tumors and matching paracancerous tissues. Tetrachloromethane (CCl4)-induced and diethylnitrosamine (DEN)-induced murine models of inflammatory hepatocarcinogenesis displayed significant hepatocellular TNF and CCR10 upregulation. Exogenous TNF applied to HepG2 and LO2 cell lines as well as wild-type (WT) mice significantly upregulated hepatocellular CCR10 expression, Akt phosphorylation, PCNA expression, and hepatocellular proliferation. Additionally, exogenous TNF significantly upregulated secretion of the natural CCR10 ligand-agonist CCL28 from both cell lines. Transgenic CCR10-knockout (CCR10 KO) in DEN-treated mice significantly increased hepatocellular apoptosis levels and significantly lowered compensatory hepatocellular proliferation but did not affect upstream TNF expression. In addition, DEN-treated CCR10 KO mice showed a significantly lower liver weight/body weight ratio, significantly lower liver tumor incidence, and significantly smaller tumors. Moreover, exogenous CCR10 expression significantly raised xenograft tumor growth in Balb/c nude mice. In vitro, CCR10 transfection or CCL28 treatment in HepG2 and LO2 cell lines significantly increased Akt phosphorylation, PCNA expression, and cell proliferation, while CCR10 silencing or Akt inhibition produced the opposite effects. In vivo, hepatocytes isolated from HCC tumor tissue and matching paracancerous tissue in DEN-treated CCR10 KO mice showed significantly lower Akt phosphorylation and PCNA expression relative to WT hepatocytes. In conclusion, inflammation-induced TNF promotes hepatocellular CCR10 expression and downstream PI3K/Akt-mediated hepatocarcinogenesis. CCR10 appears to function as a linkage between TNF stimulation and downstream PI3K/Akt pathway activation and shows promise as a potential therapeutic target for inflammation-driven HCC.

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“…These substrates are necessary for the correct intracellular signaling downstream. Therefore, AKT becomes a mediator of the activity of PI3K and is key for the control of this type of intracellular pathways [27,28].…”

Section: Discussionmentioning

confidence: 99%

Search of Allosteric Inhibitors and Associated Proteins of an AKT-like Kinase from Trypanosoma cruzi

Ochoa

Rocha-Roa

Marín-Villa

et al. 2018

IJMS

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Proteins associated to the PI3K/AKT/mTOR signaling pathway are widely used targets for cancer treatment, and in recent years they have also been evaluated as putative targets in trypanosomatids parasites, such as Trypanosoma cruzi. Here, we performed a virtual screening approach to find candidates that can bind regions on or near the Pleckstrin homology domain of an AKT-like protein in T. cruzi. The compounds were also evaluated in vitro. The in silico and experimental results allowed us to identify a set of compounds that can potentially alter the intracellular signaling pathway through the AKT-like kinase of the parasite; among them, a derivative of the pyrazolopyridine nucleus with an IC50 of 14.25 ± 1.00 μM against amastigotes of T. cruzi. In addition, we built a protein–protein interaction network of T. cruzi to understand the role of the AKT-like protein in the parasite, and look for additional proteins that can be postulated as possible novel molecular targets for the rational design of compounds against T. cruzi.

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Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt

Cited by 10 publications

References 43 publications

miR-96 exerts carcinogenic effect by activating AKT/GSK-3β/β-catenin signaling pathway through targeting inhibition of FOXO1 in hepatocellular carcinoma

miR-96 exerts carcinogenic effect by activating AKT/GSK-3β/β-catenin signaling pathway through targeting inhibition of FOXO1 in hepatocellular carcinoma

The chemokine receptor CCR10 promotes inflammation-driven hepatocarcinogenesis via PI3K/Akt pathway activation

Search of Allosteric Inhibitors and Associated Proteins of an AKT-like Kinase from Trypanosoma cruzi

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