PDK4 Protein Promotes Tumorigenesis through Activation of cAMP-response Element-binding Protein (CREB)-Ras Homolog Enriched in Brain (RHEB)-mTORC1 Signaling Cascade
PDK4 Protein Promotes Tumorigenesis through Activation of cAMP-response Element-binding Protein (CREB)-Ras Homolog Enriched in Brain (RHEB)-mTORC1 Signaling Cascade
复制标题
PDK4 蛋白通过激活 cAMP 反应元件结合蛋白 (CREB)-富含脑的 Ras 同源物 (RHEB)-mTORC1 信号级联促进肿瘤发生
DOI：
10.1074/jbc.m114.584821
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发表时间：
2014-10-24
影响因子：
4.8
通讯作者：
Zhang, Hongbing
中科院分区：
文献类型：
--
作者：
Liu, Zhibo;Chen, Xinxin;Zhang, Hongbing
背景：mTOR整合各种细胞内和细胞外信号以调节细胞生长、增殖和存活。结果：PDK 4通过激活CREB-RHEB-mTORC 1信号通路促进肿瘤发生。结论：PDK 4是一种新的mTOR信号激活剂。重要性：PDK 4激活mTORC 1可用于治疗mTOR介导的癌症和其他疾病，而雷帕霉素靶点（mTOR）整合了多种细胞内外信号，调节细胞生长和存活。已经在各种癌症中观察到mTOR的超活化。因此，mTOR活性的调节在生理过程和肿瘤发展中是重要的。在这里，我们提出丙酮酸脱氢酶激酶4（PDK 4）作为一种新的调节mTORC 1信号。在各种细胞系中，PDK 4过表达增强mTORC 1活性，而PDK 4抑制降低mTORC 1活性。此外，PDK 4与cAMP反应元件结合蛋白（CREB）结合并阻止其降解。增强的CREB因此反式激活Ras同系物的表达，丰富的大脑（RHEB），一个直接的关键激活mTORC 1，独立于AMP激活的蛋白激酶或结节性硬化症复杂蛋白2。PDK 4增强mTORC 1效应物缺氧诱导因子1和丙酮酸激酶同工酶M2，并促进有氧糖酵解（瓦尔堡效应）。PDK 4的敲低抑制了具有活化mTORC 1的癌细胞的肿瘤发展。PDK 4的丰度决定了细胞对mTOR抑制剂雷帕霉素的反应性。联合抑制mTOR和PDK 4对癌细胞增殖产生协同抑制作用。因此，PDK 4通过激活CREB-RHEB-mTORC 1信号级联促进肿瘤发生。
Background: mTOR integrates various intracellular and extracellular signals to regulate cell growth, proliferation, and survival. Results: PDK4 promotes tumorigenesis through activation of the CREB-RHEB-mTORC1 signaling cascade. Conclusion: PDK4 is a novel activator of mTOR signaling. Significance: PDK4 activation of mTORC1 may be targeted for the treatment of mTOR-mediated cancer and other diseases.Mechanistic target of rapamycin (mTOR) integrates multiple extracellular and intracellular signals to regulate cell growth and survival. Hyperactivation of mTOR has been observed in various cancers. Regulation of mTOR activity is thus of importance in physiological processes and tumor development. Here, we present pyruvate dehydrogenase kinase 4 (PDK4) as a novel regulator of mTORC1 signaling. mTORC1 activity was augmented with PDK4 overexpression and reduced by PDK4 suppression in various cell lines. Furthermore, PDK4 bound to cAMP-response element-binding protein (CREB) and prevented its degradation. The enhanced CREB consequently transactivated the expression of Ras homolog enriched in brain (RHEB), a direct key activator of mTORC1, independent of AMP-activated protein kinase or tuberous sclerosis complex protein 2. PDK4 potentiated the mTORC1 effectors hypoxia-inducible factor 1 and pyruvate kinase isozymes M2 and promoted aerobic glycolysis (Warburg effect). Knockdown of PDK4 suppressed the tumor development of cancer cells with activated mTORC1. The abundance of PDK4 dictated the responsiveness of cells to the mTOR inhibitor, rapamycin. Combinatory suppression of mTOR and PDK4 exerted synergistic inhibition on cancer cell proliferation. Therefore, PDK4 promotes tumorigenesis through activation of the CREB-RHEB-mTORC1 signaling cascade.