Cooperative activation of PDK1 and AKT by MAPK4 enhances cancer growth and resistance to therapy.
Cooperative activation of PDK1 and AKT by MAPK4 enhances cancer growth and resistance to therapy.
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DOI：
10.1371/journal.pbio.3002227
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发表时间：
2023-08
期刊：
影响因子：
9.8
通讯作者：
Yang F
中科院分区：
文献类型：
--
作者：
Han D;Wang W;Jeon JH;Shen T;Huang X;Yi P;Dong B;Yang F
磷酸肌醇依赖性激酶-1（PDK 1）是蛋白A、G和C（AGC）家族激酶的主要激酶，在调节癌细胞增殖、存活和代谢中发挥重要作用。除了以PI 3 K依赖性方式磷酸化/激活细胞膜上的AKT外，PDK 1还对许多其他AGC激酶表现出组成性活性，以促进肿瘤活性。在后一种情况下，PDK 1蛋白水平主导其活性。我们以前报道过MAPK 4是一种非典型的MAPK，可以独立于PI 3 K促进AKT激活和肿瘤生长。在这里，使用三阴性乳腺癌（TNBC）细胞模型，我们证明了MAPK 4也可以增强PDK 1蛋白合成，从而磷酸化/激活AKT以外的PDK 1底物。这种新的MAPK 4-PDK 1轴单独缺乏强有力的肿瘤促进活性，但与我们以前报道的MAPK 4-AKT轴合作促进肿瘤生长。除了增强对PI 3 K阻断的抗性之外，MAPK 4还促进癌细胞对更严格的PI 3 K和PDK 1共阻断的抗性，这是最近提出的治疗策略。目前，没有MAPK 4抑制剂来治疗MAPK 4高的癌症。基于MAPK 4-AKT和MAPK 4-PDK 1轴在促癌中的协同作用，我们预测并证实了共靶向AKT和PDK 1有效地抑制了MAPK 4诱导的癌细胞生长，这表明了治疗MAPK 4高癌症的潜在治疗策略。这项研究表明，除了激活AKT之外，MAPK 4还促进PDK 1蛋白合成，因此还激活AKT之外的PDK 1底物以促进癌症。因此，共同靶向AKT和PDK 1可以抑制MAPK 4诱导的癌细胞生长，这表明了治疗MAPK 4高癌症的潜在治疗策略，包括一大部分“三阴性”乳腺癌。
Phosphoinositide-dependent kinase-1 (PDK1) is a master kinase of the protein A, G, and C (AGC) family kinases that play important roles in regulating cancer cell proliferation, survival, and metabolism. Besides phosphorylating/activating AKT at the cell membrane in a PI3K-dependent manner, PDK1 also exhibits constitutive activity on many other AGC kinases for tumor-promoting activity. In the latter case, PDK1 protein levels dominate its activity. We previously reported that MAPK4, an atypical MAPK, can PI3K-independently promote AKT activation and tumor growth. Here, using triple-negative breast cancer (TNBC) cell models, we demonstrate that MAPK4 can also enhance PDK1 protein synthesis, thus phosphorylate/activate PDK1 substrates beyond AKT. This new MAPK4-PDK1 axis alone lacks vigorous tumor-promoting activity but cooperates with our previously reported MAPK4-AKT axis to promote tumor growth. Besides enhancing resistance to PI3K blockade, MAPK4 also promotes cancer cell resistance to the more stringent PI3K and PDK1 co-blockade, a recently proposed therapeutic strategy. Currently, there is no MAPK4 inhibitor to treat MAPK4-high cancers. Based on the concerted action of MAPK4-AKT and MAPK4-PDK1 axis in promoting cancer, we predict and confirm that co-targeting AKT and PDK1 effectively represses MAPK4-induced cancer cell growth, suggesting a potential therapeutic strategy to treat MAPK4-high cancers. This study shows that besides activating AKT, MAPK4 promotes PDK1 protein synthesis and thus also activates PDK1 substrates beyond AKT to promote cancer. Co-targeting AKT and PDK1 can therefore repress MAPK4-induced cancer cell growth, suggesting a potential therapeutic strategy to treat MAPK4-high cancers, including a large subset of "triple negative" breast cancer.
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影响因子：
50.3
作者：
Castel P;Ellis H;Bago R;Toska E;Razavi P;Carmona FJ;Kannan S;Verma CS;Dickler M;Chandarlapaty S;Brogi E;Alessi DR;Baselga J;Scaltriti M
通讯作者：
Scaltriti M
SPOP 介导的 PDK1 泛素化和降解抑制 AKT 激酶活性和致癌功能
影响因子：
37.3
作者：
Jiang Q;Zheng N;Bu L;Zhang X;Zhang X;Wu Y;Su Y;Wang L;Zhang X;Ren S;Dai X;Wu D;Xie W;Wei W;Zhu Y;Guo J
通讯作者：
Guo J
DOI：
10.1073/pnas.1005320107
发表时间：
2010-08-10
影响因子：
11.1
作者：
Furic, Luc;Rong, Liwei;Sonenberg, Nahum
通讯作者：
Sonenberg, Nahum
影响因子：
64.5
作者：
Sonenberg N;Hinnebusch AG
通讯作者：
Hinnebusch AG
影响因子：
28.2
作者：
Tan, Jing;Li, Zhimei;Yu, Qiang
通讯作者：
Yu, Qiang