4.7 Article

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

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出版社

MDPI
DOI: 10.3390/ijms231710064

关键词

LKB1; AMPK alpha; apoptosis; cisplatin; DNA damage; DNA damage response

资金

  1. JSPS KAKENHI [JP21H02691, JP21H02620]
  2. MEXT KAKENHI [JP21H00268]
  3. JST SPRING [JPMJSP2114]
  4. Takeda Science Foundation
  5. Pharmaceutical Society of Japan

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LKB1 promotes p53 activation and apoptosis induced by cisplatin in human fibrosarcoma cells, while AMPK negatively regulates p53 activation and apoptosis. Furthermore, AMPK can suppress p53 activation through oxidative stress, as shown by the cancellation of apoptosis with antioxidants in AMPK DKO cells.
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 AMPK alpha 1 and alpha 2 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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