S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDAapproved anti-helminthic agent niclosamide

Rachel L. Stewart, Brittany L. Carpenter, Dava S. West, Teresa Knifley, Lili Liu, Chi Wang, Heidi L. Weiss, Tamas S. Gal, Eric B. Durbin, Susanne M. Arnold, Kathleen L. O'Connor, Min Chen

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular invasion and decreased overall survival. In addition, depletion of S100A4 by shRNA inhibits NF-κB activity and decreases TNFα-induced MMP9 expression. Furthermore, inhibition of the NF-κB/MMP9 axis decreases lung carcinoma invasive potential. Niclosamide, a reported inhibitor of S100A4, blocks expression and function of S100A4 with a reduction in proliferation, invasion and NF-κB-mediated MMP9 expression. Collectively, this study highlights the importance of the S100A4/NF-κB/MMP9 axis in lung cancer invasion and provides a rationale for targeting S100A4 to combat lung cancer.

Original languageEnglish
Pages (from-to)34630-34642
Number of pages13
JournalOncotarget
Volume7
Issue number23
DOIs
StatePublished - Jun 7 2016

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health T32 CA160003 (RLS), T32 CA165990 (BLC), American Cancer Society Institutional Research Grant IRG-85-001-25 (MC), the National Center for Advancing Translational Sciences, National Institutes of Health UL1TR000117 (MC), the Dr. Joseph F. Pulliam Pilot Award (MC and RLS), and the National Institutes of Health R01 CA109136 (KLO). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Markey Biospecimen and Tissue Procurement, Biostatistics and Bioinformatics and Cancer Research Informatics Shared Resource Facilities assisted with the construction of tissue microarrays and clinical annotations, and are supported by National Institutes of Health P30 CA177558.

Keywords

  • FSP-1
  • MMP9
  • Metastasin-1
  • NF-κB
  • NSCLC

ASJC Scopus subject areas

  • Oncology

Fingerprint

Dive into the research topics of 'S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDAapproved anti-helminthic agent niclosamide'. Together they form a unique fingerprint.

Cite this