MCC‐555 induces apoptosis through the combination of PPARγ‐dependent and ‐independent pathways in pancreatic cancer cells

Abstract

MCC‐555 is a novel PPARα/γ dual ligand of the thiazolidinedione class that was recently developed as an anti‐diabetic drug with anti‐cancer activity. Nonsteroidal anti‐inflammatory drug (NSAID)‐activated gene (NAG‐1) is involved in pro‐apoptotic and anti‐tumorigenic properties in colorectal and lung cancer, as assessed by NAG‐1 transgenic mice; however, its roles in pancreatic cancer have not been studied. We found that MCC‐555 elicits changes of various genes such as NAG‐1, p21, and cyclin D1, which are involved in cell proliferation and apoptosis. NAG‐1 and p21 expression was not blocked by PPARγ‐specific antagonist GW9662, suggesting that MCC‐555‐induced NAG‐1 and p21 expression is independent on PPARγ activation. However, decreasing cyclin D1 by MCC‐555 seems to be affected by PPARγ activation. For NAG‐1 transcriptional regulation by MCC‐555, the GC box located in the ‐133/+41 NAG‐1 promoter plays an important for NAG‐1 transactivation by MCC‐555 and KLF4 binds to this region. Chip assay confirmed that KLF4 binds to the GC box region in the NAG‐1 promoter and regulates NAG‐1 expression in response to MCC‐555. Further, expression of KLF4 precedes NAG‐1 and p21 expression in the presence of MCC‐555. Therefore, MCC‐555′s actions on anti‐tumorigenesis involve in both PPARγ‐dependent and ‐independent pathways, thereby enhancing anti‐tumorigenesis in pancreatic cancer cells.