The FGFR1 inhibitor PD173074 induces mesenchymal-epithelial transition through the transcription factor AP-1.

Abstract

BACKGROUND:

Epithelial-mesenchymal transition (EMT) is a crucial process in cancer progression that provides cancer cells with the ability to escape from the primary focus, invade stromal tissues and migrate to distant regions. Cell lines that lack E-cadherin show increased tumorigenesis and metastasis, and the expression levels of E-cadherin and Snail correlate inversely with the prognosis of patients suffering from breast cancer or oral squamous cell carcinoma (OSCC). Moreover, recent studies have shown that most EMT cases are regulated by soluble growth factors or cytokines. Among these factors, fibroblast growth factors (FGFs) execute diverse functions by binding to and activating members of the FGF receptor (FGFR) family, including FGFR1-4. Fibroblast growth factor receptor 1 is an oncoprotein that is involved in tumorigenesis, and PD173074 is known to be a selective inhibitor of FGFR1. However, the roles of FGFR1 and FGFR1 inhibitors have not yet been examined in detail.

METHODS:

Here, we investigated the expression of FGFR1 in head and neck squamous cell carcinoma (HNSCC) and the role of the FGFR1 inhibitor PD173074 in carcinogenesis and the EMT process.

RESULTS:

Fibroblast growth factor receptor 1 was highly expressed in 54% of HNSCC cases and was significantly correlated with malignant behaviours. Nuclear FGFR1 expression was also observed and correlated well with histological differentiation, the pattern of invasion and abundant nuclear polymorphism. Fibroblast growth factor receptor 1 was also overexpressed in EMT cell lines compared with non-EMT cell lines. Furthermore, treatment of HOC313 cells with PD173074 suppressed cellular proliferation and invasion and reduced ERK1/2 and p38 activation. These cells also demonstrated morphological changes, transforming from spindle- to cobble stone-like in shape. In addition, the expression levels of certain matrix metalloproteinases (MMPs), whose genes contain activator protein-1 (AP-1) promoter sites, as well as Snail1 and Snail2 were reduced following PD173074 treatment.

CONCLUSION:

Taken together, these data suggest that PD173074 inhibits the MAPK pathway, which regulates the activity of AP-1 and induces MET. Furthermore, this induction of MET likely suppresses cancer cell growth and invasion.

• Authors: P T Nguyen, T Tsunematsu, S Yanagisawa, Y Kudo, M Miyauchi, N Kamata, T Takata
• Journal: British journal of cancer (Br J Cancer) Vol. 109 Issue 8 Pg. 2248-58 (Oct 15 2013) ISSN: 1532-1827 [Electronic] England
• PMID: 24045665 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• PD 173074
• Pyrimidines
• Transcription Factor AP-1
• FGFR1 protein, human
• MET protein, human
• Proto-Oncogene Proteins c-met
• Receptor, Fibroblast Growth Factor, Type 1
• Glycogen Synthase Kinase 3 beta
• Mitogen-Activated Protein Kinases
• Glycogen Synthase Kinase 3

Topics

• Carcinoma, Squamous Cell (drug therapy, enzymology, metabolism, pathology)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Epithelial-Mesenchymal Transition (drug effects)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Head and Neck Neoplasms (drug therapy, enzymology, metabolism, pathology)
• Humans
• Immunohistochemistry
• Mitogen-Activated Protein Kinases (metabolism)
• Neoplasm Invasiveness
• Proto-Oncogene Proteins c-met (biosynthesis)
• Pyrimidines (pharmacology)
• Receptor, Fibroblast Growth Factor, Type 1 (antagonists & inhibitors, biosynthesis)
• Squamous Cell Carcinoma of Head and Neck
• Transcription Factor AP-1 (biosynthesis, metabolism)