Critical role of peroxisome proliferator-activated receptor γ on anoikis and invasion of squamous cell carcinoma

Purpose: Peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a important role in various physiological functions. We examined whether PPAR gamma is expressed in primary squamous cell carcinoma and lymph node metastasis and whether PPAR gamma is a potential target for tumor therapy. Experimental Design and Results: A high-level expression of PPAR gamma was observed in tumor cells of human primary squamous cell carcinoma, lymph node metastasis, and Squamous cell carcinoma cell lines. Treatment with PPAR gamma-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 gamma also inhibited cell adhesion and growth of squamous cell carcinomas. The phosphorylation of focal adhesion kinase (FAK) was decreased by treatment with PPAR gamma antagonists, and resulted in decreases in phosphorylation of Erk and mitogen-activated protein kinase. Furthermore, PPAR gamma 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 alpha 5, a counter adhesion molecule for fibronectin, was inhibited by the treatment with PPAR gamma antagonists. These results indicate that the decrease in integrin alpha 5 and following inhibition of cell adhesion may cause the inhibition of FAK signaling pathways. PPAR gamma antagonists also strongly inhibited invasion of squamous cell carcinoma via down-regulation of CD151 expression. Conclusions: The cell death caused by the PPAR gamma 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 gamma function via the use of specific antagonists in the treatment of squamous cell carcinoma and the prevention of tumor invasion and metastasis.