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

• 批准号: 8695575
• 负责人: Sumin Kang
• 金额: $ 32.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695575
• 关键词: Anoikis; Antineoplastic Agents; Antisense Oligonucleotides; Apoptotic; Attenuated; Breast; CREB1 gene; Cause of Death; Cell Death; Cell Migration Induction; Cells; Cessation of life; Cisplatin; Clinical; Collaborations; Disseminated Malignant Neoplasm; Epithelial; Filopodia; Gene Expression; Genetic Transcription; Genomics; Growth; Growth Inhibitors; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; In Vitro; Lung; MAP3K5 gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mesenchymal; Molecular; Neoplasm Metastasis; Nude Mice; Organ; Patients; Phosphorylation; Primary Neoplasm; Process; Protein Kinase; Proteins; Proteomics; RPS6KA gene; Regulation; Reporting; Research; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Protein; Specimen; Tumor Cell Invasion; Vitronectin; Xenograft Model; activating transcription factor; base; cancer cell; cancer therapy; cancer type; cell motility; improved; in vivo; inhibitor/antagonist; insulin receptor substrate 1 protein; interest; malignant breast neoplasm; novel; outcome forecast; pro-apoptotic protein; protein function; public health relevance; ribosomal protein S6 kinase 2; therapeutic target; tumor; tumor progression

DESCRIPTION (provided by applicant): Metastasis is responsible for most cancer deaths, including breast, lung or head and neck cancers. However, the molecular processes underlying cellular changes that promote tumor metastasis are still poorly understood. We found that p90 Ribosomal S6 kinase 2 (RSK2) is commonly important to promote multiple steps that comprise tumor metastasis, such as resistance to anoikis induction, cell migration and invasion, and tumor metastasis in metastatic human cancers including breast, lung, and head and neck cancers. Through incorporated phosphor-proteomics and genomics based studies, we demonstrated that RSK2 mediates anti-anoikis, pro-invasive and pro-metastatic signals by phosphorylating a spectrum of downstream factors. In particular, we identified novel substrates of RSK2, including apoptosis signal-regulating kinase 1 (ASK1) and IRS1, to provide anti-anoikis protection and promote pro-invasive and pro-metastatic potentials in cancer cells, respectively. Moreover, we demonstrated that RSK2-CREB signaling pathway regulate gene expression of a group of proteins that are involved in cell death regulation including pro-apoptotic ING3 to provide anti-anoikis protection, as well as proteins that promote epithelial-mesenchymal transition (EMT) including vitronectin (VTN). These factors intertwine with each other to form a signaling network, which mediates RSK2 signals to provide a pro-survival and pro-metastatic advantage to human cancers in both transcription-dependent and -independent manners. Furthermore, our preliminary studies showed that treatment with a novel, bio-available RSK specific inhibitor, FMK-MEA significantly attenuates cancer cell invasion and tumor metastasis. Thus, our central hypothesis is that RSK2 signaling pathway is commonly activated in metastatic cancers, which provides anti-anoikis protection and promotes cancer cell invasion and tumor metastasis in both transcription-dependent and -independent manners. RSK2 signaling represents an attractive anti-metastasis therapy in cancer treatment. Three Specific Aims are proposed: (1) To determine whether RSK2 provides anti-anoikis protection to cancer cells by inhibiting a newly identified phosphorylation target ASK1 and downregulating CREB-dependent gene expression of pro-apoptotic protein ING3; (2) To determine whether RSK2 mediates pro-invasive and pro-migratory signals in cancer cells by phosphorylating pro-metastatic protein IRS1 and upregulating gene expression of EMT promoting effector VTN that is a RSK2-CREB transcription target; (3) To validate RSK2 and its signaling effectors in tumor specimens as therapeutic targets and treat human metastatic cancers in vitro and in vivo using a novel RSK inhibitor FMK-MEA in combination with anti-cancer agents including cisplatin.

描述（由申请人提供）：转移是大多数癌症死亡的原因，包括乳腺癌、肺癌或头颈癌。然而，促进肿瘤转移的细胞变化背后的分子过程仍然知之甚少。我们发现 p90 核糖体 S6 激酶 2 (RSK2) 对于促进肿瘤转移的多个步骤通常很重要，例如对失巢凋亡诱导的抵抗、细胞迁移和侵袭以及转移性人类癌症（包括乳腺癌、肺癌和头颈癌）中的肿瘤转移。通过综合磷酸蛋白质组学和基因组学研究，我们证明 RSK2 通过磷酸化一系列下游因子来介导抗失巢凋亡、促侵袭和促转移信号。特别是，我们鉴定了 RSK2 的新底物，包括凋亡信号调节激酶 1 (ASK1) 和 IRS1，分别提供抗失巢凋亡保护并促进癌细胞的促侵袭和促转移潜力。此外，我们证明RSK2-CREB信号通路调节一组参与细胞死亡调节的蛋白质的基因表达，包括提供抗失巢凋亡保护的促凋亡ING3，以及促进上皮间质转化（EMT）的蛋白质，包括玻连蛋白（VTN）。这些因子相互交织形成信号网络，介导 RSK2 信号，以转录依赖性和非转录依赖性方式为人类癌症提供促生存和促转移的优势。此外，我们的初步研究表明，使用新型生物可利用的 RSK 特异性抑制剂 FMK-MEA 进行治疗可显着减弱癌细胞侵袭和肿瘤转移。 因此，我们的中心假设是，RSK2信号通路在转移性癌症中普遍被激活，它提供抗失巢凋亡保护，并以转录依赖性和非转录依赖性方式促进癌细胞侵袭和肿瘤转移。 RSK2 信号传导代表了癌症治疗中一种有吸引力的抗转移疗法。提出了三个具体目标：（1）确定RSK2是否通过抑制新鉴定的磷酸化靶点ASK1和下调促凋亡蛋白ING3的CREB依赖性基因表达来为癌细胞提供抗失巢凋亡保护； (2) 确定RSK2是否通过磷酸化促转移蛋白IRS1并上调作为RSK2-CREB转录靶点的EMT促进效应子VTN的基因表达来介导癌细胞中的促侵袭和促迁移信号； (3) 验证肿瘤标本中的RSK2及其信号效应子作为治疗靶点，并使用新型RSK抑制剂FMK-MEA联合顺铂等抗癌药物在体外和体内治疗人类转移性癌症。