Liver kinase B1/adenosine monophosphate-activated protein kinase signaling axis induces p21/WAF1 expression in a p53-dependent manner
Liver kinase B1/adenosine monophosphate-activated protein kinase signaling axis induces p21/WAF1 expression in a p53-dependent manner
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肝激酶 B1/单磷酸腺苷激活蛋白激酶信号轴以 p53 依赖性方式诱导 p21/WAF1 表达
DOI：
10.3892/ol.2018.8741
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发表时间：
2018-07-01
期刊：
影响因子：
2.9
通讯作者：
Zhong, Diansheng
中科院分区：
文献类型：
--
作者：
Ma, Qing;Xiao, Ping;Zhong, Diansheng
肝激酶B1（LKB 1）编码丝氨酸/苏氨酸激酶，并作为肿瘤抑制剂发挥作用。LKB 1功能丧失体细胞突变经常在散发性癌症中观察到，特别是在肺癌中。异位LKB 1通过上调p21/细胞周期蛋白依赖性激酶抑制剂IA（WAFI）在LKB 1缺陷的宫颈癌和黑素瘤细胞系中诱导生长停滞。然而，潜在的分子机制仍有待阐明。本研究建立在先前的观察基础上，通过证实LKB 1的异位表达水平显著降低LKB 1缺陷型肺癌细胞的集落形成。从机制上讲，本研究表明，LKB 1过表达显着诱导p21/WAF 1的表达，在激酶依赖性的方式。相反，LKB 1稳定敲低导致结肠癌细胞中p21 WAF 1表达水平降低。此外，发现2-脱氧葡萄糖对腺苷一磷酸蛋白激酶（AMPK）的药理学活化显著增加了p21/WAFI 1的表达水平，表明AMPK在LKB 1下游起作用以诱导p21/WAFI表达。此外，目前的研究表明，功能性p53所需的p21/WAF 1诱导LKB 1。p53-Ser（15）的磷酸化通过异位LKB 1或AMPK激活而增加。总之，这些结果表明，LKB 1通过其底物AMPK以p53依赖性方式上调p21/WAF 1表达。因此，本研究确定了一个重要的信号传导轴，为LKB 1的肿瘤抑制作用提供了新的分子见解。
Liver kinase B1 (LKB1) encodes a serine/threonine kinase and functions as a tumor suppressor. LKB1 loss-of-function somatic mutations are frequently observed in sporadic types of cancer, particularly in lung cancer. Ectopic LKB1 induces growth arrest by upregulating p21/cyclin dependent kinase inhibitor IA (WAFI) in LKB1 deficient cervical and melanoma cancer cell lines. However, the underlying molecular mechanism remains to be elucidated. The present study built upon previous observations by confirming that the ectopic expression level of LKB1 significantly reduced colony formation of LKB1-deficient lung cancer cells. Mechanistically, the present study demonstrated that LKB1 overexpression significantly induced p21/WAF1 expression in a kinase-dependent manner. Conversely, LKB1 stable knockdown resulted in a decrease in p21 WAF1 expression level in colon cancer cells. In addition, it was revealed that pharmacological activation of adenosine monophosphate protein kinase (AMPK) by 2-deoxyglucose significantly increased the p21/WAF1 expression level, suggesting that AMPK acts downstream of LKB1 to induce p21/WAFI expression. Furthermore, the present study demonstrated that functional p53 was required for p21/WAF1 induction by LKB1. Phosphorylation of p53-Ser(15) was increased by ectopic LKB1 or AMPK activation. Taken together, these results suggested that LKB1 acts via its substrate, AMPK, to upregulate p21/WAF1 expression in a p53-dependent manner. Therefore, the present study identified an important signaling axis, providing novel molecular insights into the tumor suppressor role of LKB1.