Glucose starvation induces LKB1-AMPK-mediated MMP-9 expression in cancer cells.
Glucose starvation induces LKB1-AMPK-mediated MMP-9 expression in cancer cells.
复制标题
DOI：
10.1038/s41598-018-28074-w
复制
发表时间：
2018-07-04
影响因子：
4.6
通讯作者：
Tatemichi M
中科院分区：
文献类型：
--
作者：
Endo H;Owada S;Inagaki Y;Shida Y;Tatemichi M
癌细胞利用糖酵解途径来支持它们的快速生长和增殖。由于大多数实体肿瘤中的细胞受到严重的微环境压力，包括低营养和低氧气供应，这些癌细胞必须发展机制，通过代谢适应来克服这些不利的生长条件。尽管肝脏激酶B1(LKB1)-一磷酸腺苷激活的激酶(AMPK)信号通路在代谢应激条件下维持能量平衡方面起着关键作用，但LKB1-AMPK信号通路在帮助癌细胞存活和在恶性肿瘤中的作用尚未完全阐明。我们发现葡萄糖饥饿通过LKB1-AMPK调节的基质金属蛋白酶-9的表达促进癌细胞的侵袭和迁移。最有趣的是，葡萄糖饥饿诱导的氧化应激触发LKB1-AMPK信号通路促进选择性自噬，这反过来又促进Keap1的降解和随后Nrf2的激活。随后，Nrf2通过与MMP9基因启动子区域的Nrf2结合来调节MMP9的反式激活。这些机制还有助于抑制葡萄糖饥饿下的过度氧化应激，并保护细胞免于死亡。我们的数据清楚地表明，LKB1-AMPK信号不仅维持能量和氧化应激的动态平衡，而且还可以通过诱导基质金属蛋白酶-9在代谢应激条件下促进癌症的进展。
Cancer cells utilise the glycolytic pathway to support their rapid growth and proliferation. Since cells in most solid tumours are subjected to severe microenvironmental stresses including low nutrient and oxygen availability, such cancer cells must develop mechanisms to overcome these unfavourable growth conditions by metabolic adaptation. Although the liver kinase B1 (LKB1)-adenosine monophosphate-activated kinase (AMPK) signalling pathway plays a pivotal role in maintaining energy homeostasis under conditions of metabolic stress, the role of LKB1-AMPK signalling in aiding cancer cell survival and in malignant tumours has not yet been fully elucidated. We show that glucose starvation promotes cancer cell invasiveness and migration through LKB1-AMPK-regulated MMP-9 expression. Most intriguingly, triggering the LKB1-AMPK signalling pathway by glucose starvation-induced oxidative stress facilitates selective autophagy, which in turn enhances Keap1 degradation and the subsequent activation of Nrf2. Following this, Nrf2 regulates the transactivation of MMP-9 via Nrf2 binding sites in the promoter region of the MMP-9 gene. These mechanisms also contribute to the suppression of excessive oxidative stress under glucose starvation, and protect against cell death. Our data clearly shows that LKB1-AMPK signalling not only maintains energy and oxidative stress homeostasis, but could also promote cancer progression during metabolic stress conditions by MMP-9 induction.
登录
查看更多内容
AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
10.4
作者：
Endo, Hitoshi;Sugioka, Yoshihiko;Nakagi, Yoshihiko;Saijo, Yasuaki;Yoshida, Takahiko
通讯作者：
Yoshida, Takahiko
影响因子：
13.8
作者：
Kuang, Ersheng;Qi, Jianfei;Ronai, Ze'ev
通讯作者：
Ronai, Ze'ev
影响因子：
29
作者：
Hardie DG
通讯作者：
Hardie DG