The Prometastatic Ribosomal S6 Kinase 2-cAMP Response Element-binding Protein (RSK2-CREB) Signaling Pathway Up-regulates the Actin-binding Protein Fascin-1 to Promote Tumor Metastasis

• Type of Material: Article
• Authors: Dan Li, Emory University; Lingtao Jin, Emory University; Gina N. Alesi, Emory University; Young-Mee Kim, Emory University; Jun Fan, Emory University; Jae Ho Seo, Emory University; Dongsheng Wang, Emory University; Meghan Tucker, Cell Signaling Technology, Inc.; Ting-Lei Gu, Cell Signaling Technology, Inc.; Benjamin H. Lee, Novartis Institutes for BioMedical Research; Jack Taunton, University of California, San Francisco; Kelly Magliocca, Emory University; Zhuo G. Chen, Emory University; Dong M Shin, Emory University; Fadlo Khuri, Emory University; Su Kang, Emory University
• Language: English
• Date: 2013-11-08
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M113.500561
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 288
• Issue: 45
• Start Page: 32528
• End Page: 32538
• Grant/Funding Information: This work was supported in part by the American Cancer Society Grant RSG-11-081-01 (to S. K.), the National Institutes of Health/NCI SPORE in Head and Neck Cancer P50CA128613 Career Development Program Award (to S. K.), and a Robbins Scholar Award (to S. K.).; J.T. is supported by National Institutes of Health Grant GM071434.
• Keywords: Serine Threonine Protein Kinase; CANCER METASTASIS; BETA-CATENIN; TARGET; Filopodia; GENE-EXPRESSION; Biochemistry & Molecular Biology; PLASMINOGEN-ACTIVATOR INHIBITOR-1; cAMP Response Element-binding; Metastasis; TYROSINE PHOSPHORYLATION; Signal Transduction; COLON-CANCER; Cell Migration; Science & Technology; Life Sciences & Biomedicine; Cell Invasion; Ribosomal S6 Kinase 2; IN-VITRO; CREB; Fascin-1
• Research Categories: Chemistry, Biochemistry; Health Sciences, Pharmacology; Health Sciences, Oncology

Abstract

Metastasis is the leading cause of death in patients with breast, lung, and head and neck cancers. However, the molecular mechanisms underlying metastases in these cancers remain unclear. We found that the p90 ribosomal S6 kinase 2 (RSK2)- cAMP response element-binding protein (CREB) pathway is commonly activated in diverse metastatic human cancer cells, leading to up-regulation of a CREB transcription target Fascin- 1. We also observed that the protein expression patterns of RSK2 and Fascin-1 correlate in primary human tumor tissue samples from head and neck squamous cell carcinoma patients. Moreover, knockdown of RSK2 disrupts filopodia formation and bundling in highly invasive cancer cells, leading to attenuated cancer cell invasion in vitro and tumor metastasis in vivo, whereas expression of Fascin-1 significantly rescues these phenotypes. Furthermore, targeting RSK2 with the small molecule RSK inhibitor FMK-MEA effectively attenuated the invasive and metastatic potential of cancer cells in vitro and in vivo, respectively. Taken together, our findings for the first time link RSK2-CREB signaling to filopodia formation and bundling through the up-regulation of Fascin-1, providing a proinvasive and prometastatic advantage to human cancers. Therefore, protein effectors of the RSK2-CREB-Fascin-1 pathway represent promising biomarkers and therapeutic targets in the clinical prognosis and treatment of metastatic human cancers.