P90 ribosomal S6 kinase confers cancer cell survival by mediating checkpoint kinase 1 degradation in response to glucose stress.
P90 ribosomal S6 kinase confers cancer cell survival by mediating checkpoint kinase 1 degradation in response to glucose stress.
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DOI：
10.1111/cas.15168
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发表时间：
2022-01
期刊：
影响因子：
5.7
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Ma Y;Cui D;Wang L;Wang Y;Yang F;Pan H;Gong L;Zhang M;Xiong X;Zhao Y
在实体肿瘤中，癌细胞已经设计出多种方法来生存和增殖，以响应在实体肿瘤微环境中经常观察到的葡萄糖饥饿。然而，确切的机制却鲜为人知。在此，我们报告了葡萄糖剥夺激活90‐kDa核糖体S6激酶（p90 RSK），这是一种高度保守的丝氨酸/苏氨酸激酶，激活的p90 RSK促进癌细胞存活。机制上，葡萄糖剥夺激活p90 RSK使检查点激酶1 （CHK1）磷酸化，CHK1是检查点信号通路的关键传感器，在280位点磷酸化，并触发由SCFβ - TrCP泛素连接酶介导的CHK1泛素化和蛋白酶体降解，从而抑制葡萄糖剥夺诱导的癌细胞凋亡。重要的是，我们发现实体瘤肿块内p90 RSK活性与CHK1水平呈负相关，在肿瘤中心经常观察到低葡萄糖浓度，CHK1水平较低，p90 RSK活性较高。因此，我们的研究表明，p90 RSK促进CHK1 Ser280的磷酸化及其随后的降解，使癌细胞在葡萄糖剥夺的压力下逃离检查点信号，导致细胞存活，从而促进肿瘤发生。使癌细胞在葡萄糖饥饿下存活和增殖的机制尚不清楚。在此，我们报告了葡萄糖剥夺激活90 - kDa核糖体S6激酶（p90 RSK），这是一种高度保守的丝氨酸/苏氨酸激酶。激活的p90 RSK使检查点激酶1 （CHK1）磷酸化，CHK1是检查点信号通路的关键换能器，位于280位点，并触发由SCFβ - TrCP泛素连接酶介导的CHK1泛素化和蛋白酶体降解。这允许癌细胞在葡萄糖剥夺时逃离检查点信号，导致细胞存活，从而促进肿瘤发生。
In solid tumors, cancer cells have devised multiple approaches to survival and proliferate in response to glucose starvation that is often observed in solid tumor microenvironments. However, the precise mechanisms are far less known. Herein, we report that glucose deprivation activates 90‐kDa ribosomal S6 kinase (p90 RSK), a highly conserved Ser/Thr kinase, and activated p90 RSK promotes cancer cell survival. Mechanistically, activated p90 RSK by glucose deprivation phosphorylates checkpoint kinase 1 (CHK1), a key transducer in checkpoint signaling pathways, at Ser280 and triggers CHK1 ubiquitination mediated by SCFβ‐TrCP ubiquitin ligase and proteasomal degradation, subsequently suppressing cancer cell apoptosis induced by glucose deprivation. Importantly, we identified an inverse correlation between p90 RSK activity and CHK1 levels within the solid tumor mass, with lower levels of CHK1 and higher activity of p90 RSK in the center of the tumor where low glucose concentrations are often observed. Thus, our study indicates that p90 RSK promotes CHK1 phosphorylation at Ser280 and its subsequent degradation, which allows cancer cells to escape from checkpoint signals under the stress of glucose deprivation, leading to cell survival and thus contributing to tumorigenesis. The mechanisms that enable cancer cells to survive and proliferate in response to glucose starvation are poorly understood. Herein, we report that glucose deprivation activates 90‐kDa ribosomal S6 kinase (p90 RSK), a highly conserved Ser/Thr kinase. Activated p90 RSK phosphorylates checkpoint kinase 1 (CHK1), a key transducer in checkpoint signaling pathways, at Ser280 and triggers CHK1 ubiquitination mediated by SCFβ‐TrCP ubiquitin ligase and proteasomal degradation. This allows cancer cells to escape from checkpoint signals upon glucose deprivation, leading to cell survival and thus contributing to tumorigenesis.
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影响因子：
8
作者：
Ray-David, H.;Romeo, Y.;Roux, P. P.
通讯作者：
Roux, P. P.
影响因子：
78.5
作者：
Shackelford, David B.;Shaw, Reuben J.
通讯作者：
Shaw, Reuben J.
DOI：
10.1016/j.bbamcr.2011.03.012
发表时间：
2011-06
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Kim AJ;Kim HJ;Jee HJ;Song N;Kim M;Bae YS;Chung JH;Yun J
通讯作者：
Yun J
影响因子：
3.3
作者：
Li P;Goto H;Kasahara K;Matsuyama M;Wang Z;Yatabe Y;Kiyono T;Inagaki M
通讯作者：
Inagaki M
影响因子：
56.9
作者：
Bonni, A;Brunet, A;Greenberg, ME
通讯作者：
Greenberg, ME