Peroxisome proliferator-activated receptor δ confers resistance to peroxisome proliferator-activated receptor γ-induced apoptosis in colorectal cancer cells

Peroxisome proliferator-activated receptor gamma (PPAR gamma) may serve as a useful target for drug development in nondiabetic diseases. However, some colorectal cancer cells are resistant to PPAR gamma agonists by mechanisms that are poorly understood. Here, we provide the first evidence that elevated PPAR delta expression and/or activation of PPAR delta antagonize the ability of PPAR gamma to induce colorectal carcinoma cell death. More importantly, the opposing effects of PPAR delta and PPAR gamma in regulating programmed cell death are mediated by survivin and caspase-3. We found that activation of PPAR gamma results in decreased survivin expression and increased caspase-3 activity, whereas activation of PPAR delta counteracts these effects. Our findings suggest that PPAR delta and PPAR gamma coordinately regulate cancer cell fate by controlling the balance between the cell death and survival and demonstrate that inhibition of PPAR delta can reprogram PPAR gamma ligand-resistant cells to respond to PPAR gamma agonists. Oncogene (2012) 31, 1013-1023; doi:10.1038/onc.2011.299; published online 18 July 2011