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Critical Role of Peroxisome Proliferator-Activated Receptor on Anoikis and Invasion of Squamous Cell Carcinoma

Authors' Affiliations: ¹ Department of Pharmacology and ² The First Department of Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan; ³ The Third Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Japan; and ⁴ Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan

Requests for reprints: Koichiro Wada, Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-2913; Fax: 81-6-6879-2914; E-mail: kwada{at}dent.osaka-u.ac.jp.

Purpose: Peroxisome proliferator-activated receptor (PPAR) plays a important role in various physiological functions. We examined whether PPAR is expressed in primary squamous cell carcinoma and lymph node metastasis and whether PPAR is a potential target for tumor therapy.

Experimental Design and Results: A high-level expression of PPAR was observed in tumor cells of human primary squamous cell carcinoma, lymph node metastasis, and squamous cell carcinoma cell lines. Treatment with PPAR-specific antagonists, but not agonists, caused apoptotic cell death on squamous cell carcinoma cell lines in a concentration-dependent manner. Small interfering RNA for PPAR also inhibited cell adhesion and growth of squamous cell carcinomas. The phosphorylation of focal adhesion kinase (FAK) was decreased by treatment with PPAR antagonists, and resulted in decreases in phosphorylation of Erk and mitogen-activated protein kinase. Furthermore, PPAR antagonists decreased the adhesion of squamous cell carcinomas into fibronectin-coated plates, indicating the inhibition of interaction between squamous cell carcinomas and fibronectin. Expression of integrin 5, a counter adhesion molecule for fibronectin, was inhibited by the treatment with PPAR antagonists. These results indicate that the decrease in integrin 5 and following inhibition of cell adhesion may cause the inhibition of FAK signaling pathways. PPAR antagonists also strongly inhibited invasion of squamous cell carcinoma via down-regulation of CD151 expression.

Conclusions: The cell death caused by the PPAR antagonists was a result of direct interference with cell adhesion "anoikis" involving intracellular FAK signaling pathways. These results imply a potentially important and novel role for the inhibition of PPAR function via the use of specific antagonists in the treatment of squamous cell carcinoma and the prevention of tumor invasion and metastasis.

Key Words: PPAR • squamous cell carcinoma • anoikis • adhesion • invasion

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