Activation of the Akt pathway by a constitutive androstane receptor agonist results in β-catenin activation

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Activation of the Akt pathway by a constitutive androstane receptor agonist results in β-catenin activation. / Yarushkin, Andrei A.; Mazin, Mark E.; Pustylnyak, Yuliya A. et al.

In: European Journal of Pharmacology, Vol. 879, 173135, 15.07.2020.

Research output: Contribution to journal › Article › peer-review

BibTeX

@article{e654fbc78cf9476886cbd05e8a9f34a5,

title = "Activation of the Akt pathway by a constitutive androstane receptor agonist results in β-catenin activation",

abstract = "It is well known that activating the constitutive androstane receptor (CAR, NR1I3) leads to a significant proliferation of liver cells, which suggests that NR1I3 could be a therapeutic target for the partial resection of this organ. Studies describing NR1I3-mediated proliferative pathways could help determine the possible clinical applications of NR1I3 agonists during liver resection or transplantation. Recently, we reported that liver hyperplasia, which results from NR1I3 activation, is mediated by the activation of the Akt signaling pathway. In this study, we investigated the impact of the Akt signaling pathway on β-catenin and its role in liver growth. Our findings showed that NR1I3-mediated activation of the Akt pathway results in the nuclear redistribution of β-catenin and increases hepatocyte proliferation. Inhibiting the Akt pathway using the allosteric inhibitor MK-2206 decreased the amount of β-catenin in the nucleus and reduced the hepatocyte proliferation induced by a NR1I3 agonist, but promoted hypertrophic liver growth. These findings suggest that NR1I3-mediated hepatocyte proliferation and liver growth are not necessarily linked. Additionally, we found that the proliferation effect of the NR1I3-Akt-β-catenin signaling pathway is mediated, at least in part, by Cyclic D1 up-regulation. In contrast, the nuclear localization of β-catenin in response to NR1I3 did not affect the expression of the β-catenin target cMyc in the liver. In conclusion, the NR1I3-Akt signaling pathway plays a significant role in regulating hepatocyte proliferation, at least in part, by activating β-catenin.",

keywords = "Akt, Hepatomegaly, Liver, Liver hyperplasia, NR1I3, β-Catenin, TARGET, XENOSENSOR, C-MYC, ALPHA, INHIBITION, CAR, LIVER, GROWTH, GENES, beta-Catenin",

author = "Yarushkin, {Andrei A.} and Mazin, {Mark E.} and Pustylnyak, {Yuliya A.} and Prokopyeva, {Elena A.} and Pustylnyak, {Vladimir O.}",

year = "2020",

month = jul,

day = "15",

doi = "10.1016/j.ejphar.2020.173135",

language = "English",

volume = "879",

journal = "European Journal of Pharmacology",

issn = "0014-2999",

publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Activation of the Akt pathway by a constitutive androstane receptor agonist results in β-catenin activation

AU - Yarushkin, Andrei A.

AU - Mazin, Mark E.

AU - Pustylnyak, Yuliya A.

AU - Prokopyeva, Elena A.

AU - Pustylnyak, Vladimir O.

PY - 2020/7/15

Y1 - 2020/7/15

N2 - It is well known that activating the constitutive androstane receptor (CAR, NR1I3) leads to a significant proliferation of liver cells, which suggests that NR1I3 could be a therapeutic target for the partial resection of this organ. Studies describing NR1I3-mediated proliferative pathways could help determine the possible clinical applications of NR1I3 agonists during liver resection or transplantation. Recently, we reported that liver hyperplasia, which results from NR1I3 activation, is mediated by the activation of the Akt signaling pathway. In this study, we investigated the impact of the Akt signaling pathway on β-catenin and its role in liver growth. Our findings showed that NR1I3-mediated activation of the Akt pathway results in the nuclear redistribution of β-catenin and increases hepatocyte proliferation. Inhibiting the Akt pathway using the allosteric inhibitor MK-2206 decreased the amount of β-catenin in the nucleus and reduced the hepatocyte proliferation induced by a NR1I3 agonist, but promoted hypertrophic liver growth. These findings suggest that NR1I3-mediated hepatocyte proliferation and liver growth are not necessarily linked. Additionally, we found that the proliferation effect of the NR1I3-Akt-β-catenin signaling pathway is mediated, at least in part, by Cyclic D1 up-regulation. In contrast, the nuclear localization of β-catenin in response to NR1I3 did not affect the expression of the β-catenin target cMyc in the liver. In conclusion, the NR1I3-Akt signaling pathway plays a significant role in regulating hepatocyte proliferation, at least in part, by activating β-catenin.

AB - It is well known that activating the constitutive androstane receptor (CAR, NR1I3) leads to a significant proliferation of liver cells, which suggests that NR1I3 could be a therapeutic target for the partial resection of this organ. Studies describing NR1I3-mediated proliferative pathways could help determine the possible clinical applications of NR1I3 agonists during liver resection or transplantation. Recently, we reported that liver hyperplasia, which results from NR1I3 activation, is mediated by the activation of the Akt signaling pathway. In this study, we investigated the impact of the Akt signaling pathway on β-catenin and its role in liver growth. Our findings showed that NR1I3-mediated activation of the Akt pathway results in the nuclear redistribution of β-catenin and increases hepatocyte proliferation. Inhibiting the Akt pathway using the allosteric inhibitor MK-2206 decreased the amount of β-catenin in the nucleus and reduced the hepatocyte proliferation induced by a NR1I3 agonist, but promoted hypertrophic liver growth. These findings suggest that NR1I3-mediated hepatocyte proliferation and liver growth are not necessarily linked. Additionally, we found that the proliferation effect of the NR1I3-Akt-β-catenin signaling pathway is mediated, at least in part, by Cyclic D1 up-regulation. In contrast, the nuclear localization of β-catenin in response to NR1I3 did not affect the expression of the β-catenin target cMyc in the liver. In conclusion, the NR1I3-Akt signaling pathway plays a significant role in regulating hepatocyte proliferation, at least in part, by activating β-catenin.

KW - Akt

KW - Hepatomegaly

KW - Liver

KW - Liver hyperplasia

KW - NR1I3

KW - β-Catenin

KW - TARGET

KW - XENOSENSOR

KW - C-MYC

KW - ALPHA

KW - INHIBITION

KW - CAR

KW - LIVER

KW - GROWTH

KW - GENES

KW - beta-Catenin

UR - http://www.scopus.com/inward/record.url?scp=85083890779&partnerID=8YFLogxK

U2 - 10.1016/j.ejphar.2020.173135

DO - 10.1016/j.ejphar.2020.173135

M3 - Article

C2 - 32339513

AN - SCOPUS:85083890779

VL - 879

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

M1 - 173135

ER -

ID: 24092157