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

Purpose: Peroxisome proliferator-activated receptor γ (PPARγ) plays a important role in various physiological functions. We examined whether PPARγ is expressed in primary squamous cell carcinoma and lymph node metastasis and whether PPARγ is a potential target for tumor therapy. Experimental Design and Results: A high-level expression of PPARγ was observed in tumor cells of human primary squamous cell carcinoma, lymph node metastasis, and squamous cell carcinoma cell lines. Treatment with PPARγ-specific antagonists, but not agonists, caused apoptotic cell death on squamous cell carcinoma cell lines in a concentration-dependent manner. Small interfering RNA for PPARγ also inhibited cell adhesion and growth of squamous cell carcinomas. The phosphorylation of focal adhesion kinase (FAK) was decreased by treatment with PPARγ antagonists, and resulted in decreases in phosphorylation of Erk and mitogen-activated protein kinase. Furthermore, PPARγ 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 α5, a counter adhesion molecule for fibronectin, was inhibited by the treatment with PPARγ antagonists. These results indicate that the decrease in integrin α5 and following inhibition of cell adhesion may cause the inhibition of FAK signaling pathways. PPARγ antagonists also strongly inhibited invasion of squamous cell carcinoma via down-regulation of CD151 expression. Conclusions: The cell death caused by the PPARγ 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 PPARγ function via the use of specific antagonists in the treatment of squamous cell carcinoma and the prevention of tumor invasion and metastasis.