Combined inhibition of PLC{gamma}-1 and c-Src abrogates epidermal growth factor receptor-mediated head and neck squamous cell carcinoma invasion.

Abstract

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 PLCgamma-1 in the abrogation of HNSCC invasion.

EXPERIMENTAL DESIGN:

PLCgamma-1 and c-Src inhibition was achieved by a combination of small molecule inhibitors and dominant negative approaches. The effect of inhibition of PLCgamma-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 PLCgamma-1 and c-Src.

RESULTS:

Here, we show that inhibition of PLCgamma-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 PLCgamma-1 and c-Src in HNSCC cells. Combined inhibition of PLCgamma-1 and c-Src resulted in further attenuation of HNSCC cell invasion in vitro.

CONCLUSIONS:

These cumulative results suggest that PLCgamma-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.

• Authors: Hiroshi Nozawa, Gina Howell, Shinsuke Suzuki, Qing Zhang, Yanjun Qi, Judith Klein-Seetharaman, Alan Wells, Jennifer R Grandis, Sufi M Thomas
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 13 Pg. 4336-44 (Jul 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18594017 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Drug Combinations
• Enzyme Inhibitors
• Laminin
• Proteoglycans
• matrigel
• Collagen
• ErbB Receptors
• src-Family Kinases
• Phospholipase C gamma

Topics

• Antineoplastic Agents (pharmacology)
• Carcinoma, Squamous Cell (metabolism)
• Cell Line, Tumor
• Collagen (chemistry)
• Drug Combinations
• Enzyme Inhibitors (pharmacology)
• ErbB Receptors (metabolism)
• Gene Expression Regulation, Neoplastic
• Genes, Dominant
• Head and Neck Neoplasms (metabolism)
• Humans
• Laminin (chemistry)
• Models, Biological
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Phospholipase C gamma (antagonists & inhibitors)
• Proteoglycans (chemistry)
• src-Family Kinases (antagonists & inhibitors)