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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MDPI AG
2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/17/10064 |
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| author | Tatsuya Shimada Yohsuke Yabuki Takuya Noguchi Mei Tsuchida Ryuto Komatsu Shuhei Hamano Mayuka Yamada Yusuke Ezaki Yusuke Hirata Atsushi Matsuzawa |
| author_facet | Tatsuya Shimada Yohsuke Yabuki Takuya Noguchi Mei Tsuchida Ryuto Komatsu Shuhei Hamano Mayuka Yamada Yusuke Ezaki Yusuke Hirata Atsushi Matsuzawa |
| author_sort | Tatsuya Shimada |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T01:42:31Z |
| format | Article |
| id | doaj.art-a3f3212c68684a388efabc831a2ccaf2 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:42:31Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a3f3212c68684a388efabc831a2ccaf22023-11-23T13:22:18ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123171006410.3390/ijms231710064The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by CisplatinTatsuya Shimada0Yohsuke Yabuki1Takuya Noguchi2Mei Tsuchida3Ryuto Komatsu4Shuhei Hamano5Mayuka Yamada6Yusuke Ezaki7Yusuke Hirata8Atsushi Matsuzawa9Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanLiver 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.https://www.mdpi.com/1422-0067/23/17/10064LKB1AMPKαapoptosiscisplatinDNA damageDNA damage response |
| spellingShingle | Tatsuya Shimada Yohsuke Yabuki Takuya Noguchi Mei Tsuchida Ryuto Komatsu Shuhei Hamano Mayuka Yamada Yusuke Ezaki Yusuke Hirata Atsushi Matsuzawa The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin International Journal of Molecular Sciences LKB1 AMPKα apoptosis cisplatin DNA damage DNA damage response |
| 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 | LKB1 AMPKα apoptosis cisplatin DNA damage DNA damage response |
| url | https://www.mdpi.com/1422-0067/23/17/10064 |
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