Noncanonical agonist PPARγ ligands modulate the response to DNA damage and sensitize cancer cells to cytotoxic chemotherapy
| Autor: | Alexander S. Banks, Jang Hyun Choi, James C. Lo, Lawrence Kazak, Melin J. Khandekar, James P. White, Dina Laznik-Bogoslavski, Theodore M. Kamenecka, Kwok-Kin Wong, Bruce M. Spiegelman, Paul Cohen, Patrick R. Griffin |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist Male Lung Neoplasms DNA damage medicine.drug_class Amino Acid Motifs Mice Nude Antineoplastic Agents Apoptosis Ligands Carboplatin Serine 03 medical and health sciences chemistry.chemical_compound Mice Cell Line Tumor medicine Animals Humans Phosphorylation Receptor Multidisciplinary Chemistry Biological Sciences PPAR gamma 030104 developmental biology Cancer cell Cancer research Thiazolidinediones Tumor Suppressor Protein p53 DNA DNA Damage |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 115(3) |
| ISSN: | 1091-6490 |
| Popis: | The peroxisome-proliferator receptor-γ (PPARγ) is expressed in multiple cancer types. Recently, our group has shown that PPARγ is phosphorylated on serine 273 (S273), which selectively modulates the transcriptional program controlled by this protein. PPARγ 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 PPARγ 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 PPARγ 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 PPARγ physically interacts with p53 in a manner dependent on S273 phosphorylation. These data implicate a role for PPARγ in modifying the p53 response to cytotoxic therapy, which can be modulated for therapeutic gain using these compounds. |
| Databáze: | OpenAIRE |
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