PDK1 Signaling Toward PLK1-MYC Activation Confers Oncogenic Transformation, Tumor-Initiating Cell Activation, and Resistance to mTOR-Targeted Therapy
PDK1 Signaling Toward PLK1-MYC Activation Confers Oncogenic Transformation, Tumor-Initiating Cell Activation, and Resistance to mTOR-Targeted Therapy
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DOI：
10.1158/2159-8290.cd-12-0595
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发表时间：
2013-10-01
期刊：
影响因子：
28.2
通讯作者：
Yu, Qiang
中科院分区：
文献类型：
--
作者：
Tan, Jing;Li, Zhimei;Yu, Qiang
尽管 3-磷酸肌醇依赖性蛋白激酶-1 (PDK1) 主要与磷酸肌醇 3-激酶 (PI3K)-AKT 通路相关，但它也可能引发额外的信号输出以促进肿瘤发生。在此，我们报道 PDK1 直接诱导 Polo 样激酶 1 (PLK1) 磷酸化，进而诱导 MYC 磷酸化和蛋白质积累。我们发现 PDK1-PLK1-MYC 信号传导对于癌细胞的生长和存活至关重要，PDK1/PLK1 的小分子抑制为 MYC 依赖性的治疗靶向提供了有效的方法。有趣的是，PDK1-PLK1-MYC 信号传导诱导与侵袭性肿瘤行为相关的胚胎干细胞样基因特征，并且是驱动癌症干细胞 (CSC) 自我更新的强大信号轴。最后，我们发现 PLK1 抑制剂与 mTOR 抑制剂协同作用，通过拮抗代偿性 MYC 诱导，在结直肠癌中诱导协同抗肿瘤作用。这些发现确定了人类癌症和 CSC 激活的新途径，并提供了针对 MYC 相关肿瘤发生和治疗耐药的治疗策略。 意义：这项工作将 PDK1-PLK1-MYC 信号转导确定为驱动致癌转化和 CSC 自我更新的新致癌途径。 PDK1/PLK1 的靶向抑制对于靶向癌细胞中的 MYC 依赖性非常有效。因此，我们的研究结果为癌症和癌症干细胞生物学提供了重要的见解，并具有重要的治疗意义。 (c) 2013 年 AACR。
Although 3-phosphoinositide-dependent protein kinase-1 (PDK1) has been predominately linked to the phosphoinositide 3-kinase (PI3K)-AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency. Intriguingly, PDK1-PLK1-MYC signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self-renewal. Finally, we show that a PLK1 inhibitor synergizes with an mTOR inhibitor to induce synergistic antitumor effects in colorectal cancer by antagonizing compensatory MYC induction. These findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting MYC-associated tumorigenesis and therapeutic resistance.SIGNIFICANCE: This work identifies PDK1-PLK1-MYC signaling as a new oncogenic pathway driving oncogenic transformation and CSC self-renewal. Targeted inhibition of PDK1/PLK1 is robust in targeting MYC dependency in cancer cells. Thus, our findings provide important insights into cancer and CSC biology and have significant therapeutic implications. (c) 2013 AACR.