| First Author | Khandekar MJ | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 3 | Pages | 561-566 |
| PubMed ID | 29295932 | Mgi Jnum | J:257878 |
| Mgi Id | MGI:6112918 | Doi | 10.1073/pnas.1717776115 |
| Citation | Khandekar MJ, et al. (2018) Noncanonical agonist PPARgamma ligands modulate the response to DNA damage and sensitize cancer cells to cytotoxic chemotherapy. Proc Natl Acad Sci U S A 115(3):561-566 |
| abstractText | The peroxisome-proliferator receptor-gamma (PPARgamma) is expressed in multiple cancer types. Recently, our group has shown that PPARgamma is phosphorylated on serine 273 (S273), which selectively modulates the transcriptional program controlled by this protein. PPARgamma ligands, including thiazolidinediones (TZDs), block S273 phosphorylation. This activity is chemically separable from the canonical activation of the receptor by agonist ligands and, importantly, these noncanonical agonist ligands do not cause some of the known side effects of TZDs. Here, we show that phosphorylation of S273 of PPARgamma occurs in cancer cells on exposure to DNA damaging agents. Blocking this phosphorylation genetically or pharmacologically increases accumulation of DNA damage, resulting in apoptotic cell death. A genetic signature of PPARgamma phosphorylation is associated with worse outcomes in response to chemotherapy in human patients. Noncanonical agonist ligands sensitize lung cancer xenografts and genetically induced lung tumors to carboplatin therapy. Moreover, inhibition of this phosphorylation results in deregulation of p53 signaling, and biochemical studies show that PPARgamma physically interacts with p53 in a manner dependent on S273 phosphorylation. These data implicate a role for PPARgamma in modifying the p53 response to cytotoxic therapy, which can be modulated for therapeutic gain using these compounds. |
