FOXO3 induces ubiquitylation of AKT through MUL1 regulation

Sun-Yong Kim; Hyo Jeong Kim; Hyung Kwon Byeon; Dae Ho Kim; Chul-Ho Kim

doi:10.18632/oncotarget.22793

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Research Papers:

FOXO3 induces ubiquitylation of AKT through MUL1 regulation

Sun-Yong Kim, Hyo Jeong Kim, Hyung Kwon Byeon, Dae Ho Kim and Chul-Ho Kim _

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Oncotarget. 2017; 8:110474-110489. https://doi.org/10.18632/oncotarget.22793

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Abstract

Sun-Yong Kim1,*, Hyo Jeong Kim1,2,*, Hyung Kwon Byeon3,4, Dae Ho Kim1,2 and Chul-Ho Kim1,2

1Department of Otolaryngology, Ajou University School of Medicine, Suwon, Republic of Korea

2Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea

3Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea

4Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Republic of Korea

*These authors have contributed equally to this work

Correspondence to:

Chul-Ho Kim, email: [email protected]

Keywords: FOXO3; AKT; MUL1/MULAN/GIDE; ubiquitylation; cisplatin

Received: August 19, 2017 Accepted: November 16, 2017 Published: November 30, 2017

ABSTRACT

AKT (also known as protein kinase B, PKB) plays an important role in cell survival or tumor progression. For these reasons, AKT is an emerging target for cancer therapeutics. Previously our studies showed that mitochondrial E3 ubiquitin protein ligase 1 (MUL1, also known as MULAN/GIDE/MAPL) is suppressed in head and neck cancer (HNC) and acts as negative regulator against AKT. However, the MUL1 regulatory mechanisms remain largely unknown. Here we report that cisplatin (CDDP) induces thyroid cancer cell death through MUL1-AKT axis. Specifically, CDDP-induced MUL1 leads to ubiquitylation of active form of AKT. We also observed that the role of forkhead box O3 (FOXO3) is pivotal in CDDP-induced MUL1 regulation. FOXO3 knock-downed cells show resistance against CDDP-mediated MUL1-AKT axis. CDDP-mediated intracellular ROS increment plays an important role in FOXO3-MUL1-AKT signal pathway. The data provide compelling evidence to support the idea that the regulation of FOXO3-MUL1-AKT axis can be a novel strategy for the treatment of HNC with CDDP.

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Research Papers:

FOXO3 induces ubiquitylation of AKT through MUL1 regulation

Abstract