MK-2206, an allosteric inhibitor of AKT, stimulates LDLR expression and LDL uptake: A potential hypocholesterolemic agent

Bjune, Katrine; Sundvold, Hilde; Leren, Trond P.; Naderi, Soheil

doi:10.1016/j.atherosclerosis.2018.07.009

Cited by 14 publications

(17 citation statements)

References 41 publications

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“…To examine the effect of these inhibitors on LDLR gene transcription, we cultured HepG2 cells that were transfected with the pLR1563-luc plasmid, a luciferase reporter construct driven by the LDLR promoter, in the absence or presence of the AKT inhibitors for 14 h and then examined them for luciferase activity. As expected, luciferase activity was induced in cells that were treated with MK-2206, whereas triciribine had no effect on luciferase activity (Fig 2B) [16, 17]. Interestingly, all the other AKT inhibitors also exerted a positive effect on luciferase activity.…”

Section: Resultssupporting

confidence: 67%

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Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms

2019

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Protein kinase B (AKT) is a serine/threonine kinase that functions as an important downstream effector of phosphoinositide 3-kinase. We have recently shown that MK-2206 and triciribine, two highly selective AKT inhibitors increase the level of low density lipoprotein receptor (LDLR) mRNA which leads to increased amount of cell-surface LDLRs. However, whereas MK-2206 induces transcription of the LDLR gene, triciribine stabilizes LDLR mRNA, raising the possibility that the two inhibitors may actually affect other kinases than AKT. In this study, we aimed to ascertain the role of AKT in regulation of LDLR mRNA expression by examining the effect of five additional AKT inhibitors on LDLR mRNA levels. Here we show that in cultured HepG2 cells, AKT inhibitors ARQ-092, AKT inhibitor VIII, perifosine, AT7867 and CCT128930 increase LDLR mRNA levels by inducing the activity of LDLR promoter. CCT128930 also increased the stability of LDLR mRNA. To study the role of AKT isoforms on LDLR mRNA levels, we examined the effect of siRNA-mediated knockdown of AKT1 or AKT2 on LDLR promoter activity and LDLR mRNA stability. Whereas knockdown of either AKT1 or AKT2 led to upregulation of LDLR promoter activity, only knockdown of AKT2 had a stabilizing effect on LDLR mRNA. Taken together, these results provide strong evidence for involvement of AKT in regulation of LDLR mRNA expression, and point towards the AKT isoform specificity for upregulation of LDLR mRNA expression.

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Section: Resultssupporting

confidence: 67%

“…We have recently shown that two pharmacologic inhibitors of AKT, MK-2206 and triciribine, increase the levels of LDLR mRNA, leading to increased levels of cell-surface LDLRs [16, 17]. Interestingly, we found that MK-2206 and triciribine utilize two different regulatory mechanisms to trigger the accumulation of LDLR mRNA.…”

Section: Introductionmentioning

confidence: 91%

Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms

2019

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“…The levels of LDLR on the cell surface and internalization of LDL were measured by flow cytometry as previously described 56 .…”

Section: Methodsmentioning

confidence: 99%

Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA

Bjune

Wierød

Naderi

2018

Sci Rep

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Low-density lipoprotein receptor (LDLR) is a key regulator of the metabolism of plasma low-density lipoprotein cholesterol (LDL-C), the elevated levels of which are associated with an increased risk of cardiovascular disease. Therefore, enhancing LDLR expression represents a potent treatment strategy for hypercholesterolemia. Here, we report that in cultured human hepatoma cells, triciribine, a highly selective AKT inhibitor, increases the stability of LDLR mRNA, an event that translates into upregulation of cell-surface LDLR levels and induction of cellular LDL uptake. This effect of triciribine requires ERK activity and is partially dependent on the intervening sequence between the AU-rich elements ARE3 and ARE4 in LDLR 3′UTR. We also show that triciribine downregulates the expression of PCSK9 mRNA and blunts the secretion of its protein. Notably, triciribine was found to potentiate the effect of mevastatin on LDLR protein levels and activity. We also show that primary human hepatocytes respond to triciribine by increasing the expression of LDLR. Furthermore, a pilot experiment with mice revealed that a two-weeks treatment with triciribine significantly induced the hepatic expression of LDLR protein. These results identify triciribine as a novel LDLR-elevating agent and warrant further examination of its potential as a hypocholesterolemic drug either as monotherapy or in combination with statins.

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“…It was investigated in several clinical trials. The potential use of MK-2206 goes beyond oncology, demonstrating a significant reduction of plasma LDL-cholesterol levels in cultured hepatic cells ( 163 ).…”

Section: Akt Inhibitors In Clinical Studiesmentioning

confidence: 99%

The Akt pathway in oncology therapy and beyond (Review)

et al. 2018

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Protein kinase B (Akt), similar to many other protein kinases, is at the crossroads of cell death and survival, playing a pivotal role in multiple interconnected cell signaling mechanisms implicated in cell metabolism, growth and division, apoptosis suppression and angiogenesis. Akt protein kinase displays important metabolic effects, among which are glucose uptake in muscle and fat cells or the suppression of neuronal cell death. Disruptions in the Akt-regulated pathways are associated with cancer, diabetes, cardiovascular and neurological diseases. The regulation of the Akt signaling pathway renders Akt a valuable therapeutic target. The discovery process of Akt inhibitors using various strategies has led to the identification of inhibitors with great selectivity, low side-effects and toxicity. The usefulness of Akt emerges beyond cancer therapy and extends to other major diseases, such as diabetes, heart diseases, or neurodegeneration. This review presents key features of Akt structure and functions, and presents the progress of Akt inhibitors in regards to drug development, and their preclinical and clinical activity in regards to therapeutic efficacy and safety for patients.

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MK-2206, an allosteric inhibitor of AKT, stimulates LDLR expression and LDL uptake: A potential hypocholesterolemic agent

Abstract: MK-2206 is a novel LDLR-inducing agent that, either alone or in combination with statins, exerts a stimulating effect on cellular LDL uptake.

Cited by 14 publications

References 41 publications

Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms

Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms

Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA

The Akt pathway in oncology therapy and beyond (Review)

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