Inhibition of tumorigenesis by peroxisome proliferator-activated receptor (PPAR)-dependent cell cycle blocks in human skin carcinoma cells

To examine the functional role of peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) and PPAR gamma in skin cancer, stable cell lines were created in the A431 human squamous cell carcinoma cell line. Expression of PPAR target genes was greatly enhanced in response to ligand activation of PPAR beta/delta or PPAR gamma in A431 cells expressing these receptors. PPAR beta/delta expression blocked the cell cycle at the G2/M phase, and this effect was increased by ligand activation. Ligand activation of PPAR beta/delta markedly inhibited clonogenicity as compared to vehicle-treated controls. Similarly, ligand activation of PPAR gamma in A431 cells expressing PPAR gamma resulted in reduced clonogenicity. Expression of either PPAR beta/delta or PPAR gamma markedly reduced tumor volume in ectopic xenografts, while ligand activation of these receptors had little further influence on tumor volume. Collectively, these studies demonstrate that stable expression and activation of PPAR beta/delta or PPAR gamma in A431 cells led to reduced tumorigenicity. Importantly, PPAR expression or ligand activation had major impacts on clonogenicity and/or tumor volume. Thus, PPAR beta/delta or PPAR gamma could be therapeutically targeted for the treatment of squamous cell carcinomas.