Transcription-dependent and -independent signaling of RSK2 in cancer metastasis

癌症转移中 RSK2 的转录依赖性和非依赖性信号传导

基本信息

批准号：
10379092
负责人：
Sumin Kang
金额：
$ 36.31万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379092
关键词：
AMP-activated protein kinase kinase Anoikis Attenuated Biological Biological Process CREB1 gene Cause of Death Cell Death Cells Cessation of life Clinical Clinical Treatment Combined Modality Therapy Complex Data Disseminated Malignant Neoplasm Enzymes Genetic Genetic Transcription Glutamate Dehydrogenase Glutamates Homeostasis Human IRS1 gene In Vitro Link Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic Metabolic Pathway Metabolism Neoplasm Metastasis Oxidation-Reduction Pathway interactions Patients Pattern Pharmacology Phosphorylation Play Process Production Proliferating Property Proteins RPS6KA gene Reporting Research Resistance Ribosomal Protein S6 Kinase Ribosomes Role STK11 gene Series Signal Pathway Signal Transduction Testing Therapeutic Therapeutic Effect Treatment Efficacy Variant anti-cancer attenuation cancer cell cancer type cell type in vivo inhibitor knock-down lung cancer cell metabolic abnormality assessment metastatic process migration neoplastic cell novel patient derived xenograft model small molecule inhibitor stathmin transcription factor tumor upstream kinase

项目摘要

Metastasis is a complex biological process, which involves multiple signaling pathways. Therefore, a single agent is often insufficient and combination therapy is vitally important in the successful treatment of metastatic cancer. We reported that p90 ribosomal S6 kinase 2 (RSK2) promotes metastasis by activating multiple downstream substrates. In addition, we recently identified that glutamate dehydrogenase 1 (GDH1), a critical enzyme in the glutaminolysis pathway, provides anti-anoikis signals by activating CamKK2 and its downstream AMPK to regulate energy production, protecting cells from anoikis, and promoting metastasis in lung cancer. The effect of GDH1 is evident in LKB1-deficient cancer, where AMPK activation predominantly depends on CamKK2. This suggests that RSK2 and GDH1 are promising anti-metastasis targets. Indeed, targeting RSK2 or GDH1 by fmk (identified by our collaborator Jack Taunton at UCSF) or R162 (identified by our group) attenuated metastasis. We recently found that genetic or pharmacological inhibition of these two distinct signaling axes results in synergistic attenuation of cell invasion, migration, and anoikis resistance in LKB1-deficient lung cancer. Biological and metabolic studies revealed that the combined therapy further attenuates CREB activation. Intriguingly, GDH1 knockdown resulted in decreased activity of CamK4, another upstream kinase of CREB, suggesting that combined targeting of RSK2 and GDH1 may further attenuate CREB activity by inhibiting RSK2 and GDH1-CamKK2-CamK4 signaling involved CREB phosphorylation. In addition, combined targeting of RSK2 and GDH1 synergistically induced anoikis in LKB1 wild-type (wt) expressing cells and RSK2 directly phosphorylated LKB1, leading to AMPK activation. These data suggest that RSK2 may signal through LKB1 and AMPK to contribute to anoikis resistance in LKB1 wt cells. Thus, we hypothesize that RSK2 and GDH1 coordinately regulates AMPK and CREB in transcription- dependent and -independent manners to provide pro-metastatic potential in cancer cells. Thus, targeting both cellular and metabolic signaling by combination of RSK2 and GDH1 inhibitors is a promising anti-metastasis therapeutic strategy. We will use lung cancer with LKB1 or LKB1 null as a research platform. Three specific aims are proposed: (1) To demonstrate whether RSK2 and GDH1 coordinately provides anti-anoikis protection to cancer cells by activating AMPK through LKB1 and CamKK2, respectively; (2) To determine whether RSK2 and GDH1 together mediates migratory and pro-invasive signals by activating CREB and CREB transcription targets; (3) To validate whether RSK2 and GDH1 signaling correlates with metastatic potential in patient tumors and evaluate the therapeutic efficacy of targeting RSK2 and GDH1 in combination in treatment of metastatic cancers.

转移是一个复杂的生物学过程，涉及多个信号通路。因此，单个代理通常不足，联合疗法在成功治疗转移性癌症中至关重要。我们报道P90核糖体S6激酶2（RSK2）通过激活多个下游促进转移基材。此外，我们最近确定了谷氨酸脱氢酶1（GDH1），这是一种关键酶谷氨酰胺溶解途径，通过激活CAMKK2及其下游AMPK来提供抗Anoikis信号调节能源生产，保护细胞免受厌食症的影响，并促进肺癌的转移。效果 GDH1在LKB1缺陷癌症中很明显，其中AMPK激活主要取决于CAMKK2。这表明RSK2和GDH1是有前途的抗近时间靶标。确实，FMK靶向RSK2或GDH1 （由我们在UCSF的合作者Jack Taunton确定）或R162（由我们的小组确定）减弱转移。我们最近发现，这两个不同信号轴的遗传学或药理抑制导致 LKB1缺陷肺癌中细胞侵袭，迁移和抗厌氧菌抗性的协同衰减。生物学和代谢研究表明，联合治疗进一步减轻了CREB的激活。有趣的是，GDH1敲低导致CAMK4的活性下降，CREB的另一种上游激酶，提示RSK2和GDH1的联合靶向可以通过抑制RSK2进一步减弱CREB活性和GDH1-CAMKK2-CAMK4信号传导涉及CREB磷酸化。另外，RSK2的联合靶向和GDH1在LKB1野生型（WT）中协同诱导了ANOIKI，直接表达细胞和RSK2 磷酸化的LKB1，导致AMPK激活。这些数据表明RSK2可能通过LKB1发出信号 AMPK有助于LKB1 WT细胞中的阳极抗性。因此，我们假设RSK2和GDH1在转录中协调调节AMPK和CREB 依赖和非依赖性的举止，以在癌细胞中提供促可能性潜力。因此，针对两者通过RSK2和GDH1抑制剂的组合，细胞和代谢信号传导是一种有希望治疗策略。我们将将肺癌与LKB1或LKB1 NULL一起使用作为研究平台。三个具体目标提出：（1）证明RSK2和GDH1是否协调为抗Anoikis保护通过通过LKB1和CAMKK2激活AMPK来激活癌细胞；（2）确定RSK2和是否是否 GDH1通过激活CREB和CREB转录靶标共同介导迁移和促侵入性信号。（3）验证RSK2和GDH1信号传导是否与患者肿瘤中的转移潜力相关评估靶向RSK2和GDH1在转移性癌症治疗中的治疗功效。