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The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin

Liver kinase B1 (LKB1) is a serine/threonine protein kinase that acts as a key tumor suppressor protein by activating its downstream kinases, such as AMP-activated protein kinase (AMPK). However, the regulatory actions of LKB1 and AMPK on DNA damage response (DDR) remain to be explored. In this stud...

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Autores principales: Shimada, Tatsuya, Yabuki, Yohsuke, Noguchi, Takuya, Tsuchida, Mei, Komatsu, Ryuto, Hamano, Shuhei, Yamada, Mayuka, Ezaki, Yusuke, Hirata, Yusuke, Matsuzawa, Atsushi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456506/
https://www.ncbi.nlm.nih.gov/pubmed/36077459
http://dx.doi.org/10.3390/ijms231710064
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author Shimada, Tatsuya
Yabuki, Yohsuke
Noguchi, Takuya
Tsuchida, Mei
Komatsu, Ryuto
Hamano, Shuhei
Yamada, Mayuka
Ezaki, Yusuke
Hirata, Yusuke
Matsuzawa, Atsushi
author_facet Shimada, Tatsuya
Yabuki, Yohsuke
Noguchi, Takuya
Tsuchida, Mei
Komatsu, Ryuto
Hamano, Shuhei
Yamada, Mayuka
Ezaki, Yusuke
Hirata, Yusuke
Matsuzawa, Atsushi
author_sort Shimada, Tatsuya
collection PubMed
description Liver kinase B1 (LKB1) is a serine/threonine protein kinase that acts as a key tumor suppressor protein by activating its downstream kinases, such as AMP-activated protein kinase (AMPK). However, the regulatory actions of LKB1 and AMPK on DNA damage response (DDR) remain to be explored. In this study, we investigated the function of LKB1 in DDR induced by cisplatin, a representative DNA-damaging agent, and found that LKB1 stabilizes and activates p53 through the c-Jun N-terminal kinase (JNK) pathway, which promotes cisplatin-induced apoptosis in human fibrosarcoma cell line HT1080. On the other hand, we found that AMPKα1 and α2 double knockout (DKO) cells showed enhanced stabilization of p53 and increased susceptibility to apoptosis induced by cisplatin, suggesting that AMPK negatively regulates cisplatin-induced apoptosis. Moreover, the additional stabilization of p53 and subsequent apoptosis in AMPK DKO cells were clearly canceled by the treatment with the antioxidants, raising the possibility that AMPK suppresses the p53 activation mediated by oxidative stress. Thus, our findings unexpectedly demonstrate the reciprocal regulation of p53 by LKB1 and AMPK in DDR, which provides insights into the molecular mechanisms of DDR.
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spelling pubmed-94565062022-09-09 The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin Shimada, Tatsuya Yabuki, Yohsuke Noguchi, Takuya Tsuchida, Mei Komatsu, Ryuto Hamano, Shuhei Yamada, Mayuka Ezaki, Yusuke Hirata, Yusuke Matsuzawa, Atsushi Int J Mol Sci Article Liver kinase B1 (LKB1) is a serine/threonine protein kinase that acts as a key tumor suppressor protein by activating its downstream kinases, such as AMP-activated protein kinase (AMPK). However, the regulatory actions of LKB1 and AMPK on DNA damage response (DDR) remain to be explored. In this study, we investigated the function of LKB1 in DDR induced by cisplatin, a representative DNA-damaging agent, and found that LKB1 stabilizes and activates p53 through the c-Jun N-terminal kinase (JNK) pathway, which promotes cisplatin-induced apoptosis in human fibrosarcoma cell line HT1080. On the other hand, we found that AMPKα1 and α2 double knockout (DKO) cells showed enhanced stabilization of p53 and increased susceptibility to apoptosis induced by cisplatin, suggesting that AMPK negatively regulates cisplatin-induced apoptosis. Moreover, the additional stabilization of p53 and subsequent apoptosis in AMPK DKO cells were clearly canceled by the treatment with the antioxidants, raising the possibility that AMPK suppresses the p53 activation mediated by oxidative stress. Thus, our findings unexpectedly demonstrate the reciprocal regulation of p53 by LKB1 and AMPK in DDR, which provides insights into the molecular mechanisms of DDR. MDPI 2022-09-02 /pmc/articles/PMC9456506/ /pubmed/36077459 http://dx.doi.org/10.3390/ijms231710064 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Shimada, Tatsuya
Yabuki, Yohsuke
Noguchi, Takuya
Tsuchida, Mei
Komatsu, Ryuto
Hamano, Shuhei
Yamada, Mayuka
Ezaki, Yusuke
Hirata, Yusuke
Matsuzawa, Atsushi
The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin
title The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin
title_full The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin
title_fullStr The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin
title_full_unstemmed The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin
title_short The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin
title_sort distinct roles of lkb1 and ampk in p53-dependent apoptosis induced by cisplatin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456506/
https://www.ncbi.nlm.nih.gov/pubmed/36077459
http://dx.doi.org/10.3390/ijms231710064
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