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Combined Inhibition of PLC-1 and c-Src Abrogates Epidermal Growth Factor Receptor–Mediated Head and Neck Squamous Cell Carcinoma Invasion

Authors' Affiliations: ¹ Department of Oral and Maxillofacial Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan and Departments of ² Otolaryngology, ³ Pharmacology, ⁴ School of Computer Science, ⁵ Structural Biology, and ⁶ Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute; and ⁷ Language Technologies Institute, Carnegie Mellon University, Pittsburgh, Pennsylvania

Requests for reprints: Sufi Mary Thomas, 203 Lothrop Street, Room 100, Pittsburgh, PA 15213. Phone: 412-647-0166; Fax: 412-647-0108; E-mail: smt30{at}pitt.edu.

Purpose: Mortality from head and neck squamous cell carcinoma (HNSCC) is usually associated with locoregional invasion of the tumor into vital organs, including the airway. Understanding the signaling mechanisms that abrogate HNSCC invasion may reveal novel therapeutic targets for intervention. The purpose of this study was to investigate the efficacy of combined inhibition of c-Src and PLC-1 in the abrogation of HNSCC invasion.

Experimental Design: PLC-1 and c-Src inhibition was achieved by a combination of small molecule inhibitors and dominant negative approaches. The effect of inhibition of PLC-1 and c-Src on invasion of HNSCC cells was assessed in an in vitro Matrigel-coated transwell invasion assay. In addition, the immunoprecipitation reactions and in silico database mining was used to examine the interactions between PLC-1 and c-Src.

Results: Here, we show that inhibition of PLC-1 or c-Src with the PLC inhibitor U73122 or the Src family inhibitor AZD0530 or using dominant-negative constructs attenuated epidermal growth factor (EGF)–stimulated HNSCC invasion. Furthermore, EGF stimulation increased the association between PLC-1 and c-Src in HNSCC cells. Combined inhibition of PLC-1 and c-Src resulted in further attenuation of HNSCC cell invasion in vitro.

Conclusions: These cumulative results suggest that PLC-1 and c-Src activation contribute to HNSCC invasion downstream of EGF receptor and that targeting these pathways may be a novel strategy to prevent tumor invasion in HNSCC.

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