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Author Notes:

To whom correspondence should be addressed: Sumin Kang, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Rd. NE, Atlanta, GA 30322. Tel.: 1-404-778-1880; Fax: 1-404-778-5520; E-mail: smkang@emory.edu.

We thank Jeannette Taylor at Emory University Electron Microscopy Core for assistance with scanning electron microscopy. We thank Jong Seok Lee for technical support. We acknowledge the microscope core facility at the Winship Cancer Institute of Emory University.

M. T. and T.-L. G. are employees of Cell Signaling Technology, Inc. J. T. is as an inventor on a patent application filed by the University of California that describes the RSK inhibitor FMK.

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Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Invasion
  • Cell Migration
  • Metastasis
  • Serine Threonine Protein Kinase
  • Signal Transduction
  • Fascin-1
  • Ribosomal S6 Kinase 2
  • cAMP Response Element-binding
  • Filopodia
  • PLASMINOGEN-ACTIVATOR INHIBITOR-1
  • CANCER METASTASIS
  • BETA-CATENIN
  • TYROSINE PHOSPHORYLATION
  • GENE-EXPRESSION
  • COLON-CANCER
  • IN-VITRO
  • CREB
  • TARGET

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

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Journal Title:

Journal of Biological Chemistry

Volume:

Volume 288, Number 45

Publisher:

, Pages 32528-32538

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

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