A novel AKT inhibitor, AZD5363, inhibits phosphorylation of AKT downstream molecules, and activates phosphorylation of mTOR and SMG-1 dependent on the liver cancer cell type

Zhang, Yuncheng; Zheng, Yan; Faheem, Ali; Sun, Tiantong; Li, Chunyou; Li, Zhe; Zhao, Diantang; Wu, Chao; Li, Jun

doi:10.3892/ol.2016.4111

Cited by 25 publications

(21 citation statements)

References 42 publications

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“…We chose to test the effects of two AKT inhibitors, AZD5363 (AZD) and MK2206-HCl (MK), on synaptic plasticity. AZD and MK have different mechanisms of action; AZD is an ATP-competitive AKT inhibitor ( Zhang et al, 2016 ) and MK is an allosteric AKT inhibitor ( Liu et al, 2011 ). To examine AZD and MK action in the brain, we first assessed their effects on the phosphorylation of AKT and a well-characterized downstream target of AKT, glycogen synthase kinase 3β (GSK-3β) in hippocampal slices.…”

Section: Resultsmentioning

confidence: 99%

AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity

Levenga

Wong

Milstead

et al. 2017

eLife

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AKT is a kinase regulating numerous cellular processes in the brain, and mutations in AKT are known to affect brain function. AKT is indirectly implicated in synaptic plasticity, but its direct role has not been studied. Moreover, three highly related AKT isoforms are expressed in the brain, but their individual roles are poorly understood. We find in Mus musculus, each AKT isoform has a unique expression pattern in the hippocampus, with AKT1 and AKT3 primarily in neurons but displaying local differences, while AKT2 is in astrocytes. We also find isoform-specific roles for AKT in multiple paradigms of hippocampal synaptic plasticity in area CA1. AKT1, but not AKT2 or AKT3, is required for L-LTP through regulating activity-induced protein synthesis. Interestingly, AKT activity inhibits mGluR-LTD, with overlapping functions for AKT1 and AKT3. In summary, our studies identify distinct expression patterns and roles in synaptic plasticity for AKT isoforms in the hippocampus.

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Section: Resultsmentioning

confidence: 99%

AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity

Levenga

Wong

Milstead

et al. 2017

eLife

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“…The PI3K/Akt/mTOR signalling pathway is important for cell proliferation. However, due to its frequent dysregulation, Akt is typically accepted as a promising anticancer therapeutic target ( 17 ). This signalling pathway is activated by various extracellular growth factors, including epidermal growth factor, insulin-like growth factor 1 and insulin, and simulates downstream mTOR signalling ( 18 ).…”

Section: Resultsmentioning

confidence: 99%

Cardiac progenitor cell‑derived exosomes promote H9C2 cell growth via Akt/mTOR activation

Jiang

Yang

et al. 2018

Int J Mol Med

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Exosomes are cell-derived vesicles released from a variety of mammalian cells that are involved in cell-to-cell signalling. It has been reported that cardiac progenitor cells (CPCs) derived from an adult heart are one of the most promising stem cell types for cardioprotection and repair. The mammalian target of rapamycin (mTOR) signalling pathway is a pivotal regulator in CPCs, therefore, CPC-derived exosomes were used in the present study to investigate whether it can promote H9C2 cell growth through the protein kinase B (PKB, or Akt)/mTOR signalling pathway. The CPCs were isolated from Sprague-Dawley hearts. Following treatment with a specific medium, the exosomes were purified and identified by electron micrograph and western blot assays, using CD63 and CD81 as markers. The methyl-thiazolyl-tetrazolium and 5-ethynyl-2′-deoxyuridine methods were used to detect H9C2 cell growth. The expression of Akt and mTOR were detected by western blot analysis following treatment with 200 or 400 µg/ml of exosomes for 24 or 48 h, respectively. It was found that, compared with higher concentrations of exosomes, prolonging the duration of exposure promoted cell growth. Accordingly, CPC-derived exosomes stimulated the expression of Akt to a marked degree; groups treated with exosomes for 48 h showed higher expression of Akt than those treated for 24 h at the same concentration. mTOR was also stimulated by CPC-derived exosomes. The activation of mTOR increased in accordance with the treatment time at an exosome concentration of 200 µg/ml and decreased with treatment time at an exosome concentration of 400 µg/ml. In conclusion, the present study demonstrated that CPC-derived exosomes promoted H9C2 cell growth via the activation of Akt/mTOR in a time-dependent manner at a relatively low exosome concentration, which may provide a novel therapy for cardiovascular disease.

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“…We chose to test the effects of two AKT inhibitors, AZD5363 (AZD) and MK2206-HCl (MK), on synaptic plasticity. AZD and MK have different mechanisms of action; AZD is an ATP-competitive AKT inhibitor 17 and MK is an allosteric AKT inhibitor 18 . To examine AZD and MK action in the brain, we first assessed their effects on the phosphorylation of AKT and a well-characterized downstream target of AKT, glycogen synthase kinase 3β (GSK-3β) in hippocampal slices.…”

Section: Resultsmentioning

confidence: 99%

AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity

Levenga

Wong

Milstead

et al. 2017

Preprint

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13AKT is a kinase that regulates numerous cellular processes in the brain and mutations in AKT 14 are known to affect brain function. AKT is indirectly implicated in synaptic plasticity, but its direct 15 role has not been studied. Moreover, three highly related AKT isoforms are expressed in the 16 brain, but their individual roles are poorly understood. We find that each AKT isoform has a 17 unique expression pattern in the hippocampus, with AKT1 and AKT3 primarily in neurons but 18 displaying local differences, while AKT2 is in astrocytes. We also find isoform-specific roles for 19 AKT in multiple paradigms of hippocampal synaptic plasticity. AKT1, but not AKT2 or AKT3, is 20 required for L-LTP through regulating activity-induced protein synthesis. Interestingly, AKT 21 activity inhibits mGluR-LTD, with overlapping functions for AKT1 and AKT3. In summary, our 22

show abstract

A novel AKT inhibitor, AZD5363, inhibits phosphorylation of AKT downstream molecules, and activates phosphorylation of mTOR and SMG-1 dependent on the liver cancer cell type

Cited by 25 publications

References 42 publications

AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity

AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity

Cardiac progenitor cell‑derived exosomes promote H9C2 cell growth via Akt/mTOR activation

AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity

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