Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Suppression of FoxO6 by lipopolysaccharide in aged rat liver

Dae Hyun Kim, Min Hi Park, Ki Wung Chung, Min Jo Kim, Daeui Park, Bonggi Lee, Eun Kyeong Lee, Yeon Ja Choi, Nam Deuk Kim, Byung Pal Yu and Hae Young Chung _

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Oncotarget. 2015; 6:34143-34157. https://doi.org/10.18632/oncotarget.6219

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Abstract

Dae Hyun Kim1, Min Hi Park1, Ki Wung Chung1, Min Jo Kim1, Daeui Park2, Bonggi Lee1, Eun Kyeong Lee1, Yeon Ja Choi1, Nam Deuk Kim1, Byung Pal Yu3 and Hae Young Chung1

1 Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Gumjung-gu, Busan, Korea

2 In silico Toxicology Research Center, Korea Institute of Toxicology, Daejeon, Korea

3 Department of Physiology, The University of Texas Health Science Center at San Antonio, TX, USA

Correspondence to:

Hae Young Chung, email:

Keywords: FoxO6, Pak1 pathway, aging, NF-κB, Akt, Gerotarget

Received: August 03, 2015 Accepted: September 15, 2015 Published: October 24, 2015

Abstract

The beneficial role of FoxO during aging has been proposed for its promotion of resistance to oxidative stress and inhibition of pro-inflammatory mediators. On the other hand, NF-κB is a pro-inflammatory transcription factor which is a key mediator of inflammatory cytokine generation. However, the correlation between FoxO6 and NF-κB during aging has not fully been explored.

The main purpose of the present study was to elucidate mechanisms underlying the protective role of FoxO6 in the maintenance of cellular homeostasis under potent pro-inflammatory conditions induced by LPS. Initial experimentation revealed that reduced FoxO6 activity during aging was caused by its phosphorylation, which suppressed its transcriptional activity in aged livers. Transfection with FoxO6-wt virus and FoxO6-siRNA in HepG2 cells revealed that FoxO6 phosphorylation by LPS leads to NF-κB activation via Akt and Pak1 pathways. Furthermore, Pak1 activity was increased in a phosphatidylinositol 3-kinase independent manner, and LPS-induced FoxO6 phosphorylation and FoxO6 inactivation were Pak1-dependent in nuclear fractions of cells. Further revealed Pak1 phosphorylation by LPS permitted interaction between FoxO6 and Akt.

Current study suggests FoxO6 phosphorylation facilitates the nuclear translocation of NF-κB via Akt and Pak1 pathways induced by LPS in aged rats.


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