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Noncanonical agonist PPAR? ligands modulate the response to DNA damage and sensitize cancer cells to cytotoxic chemotherapy.

ABSTRACT: The peroxisome-proliferator receptor-? (PPAR?) is expressed in multiple cancer types. Recently, our group has shown that PPAR? is phosphorylated on serine 273 (S273), which selectively modulates the transcriptional program controlled by this protein. PPAR? 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 PPAR? 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 PPAR? 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 PPAR? physically interacts with p53 in a manner dependent on S273 phosphorylation. These data implicate a role for PPAR? in modifying the p53 response to cytotoxic therapy, which can be modulated for therapeutic gain using these compounds.

SUBMITTER: Khandekar MJ

PROVIDER: S-EPMC5776997 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Noncanonical agonist PPARγ ligands modulate the response to DNA damage and sensitize cancer cells to cytotoxic chemotherapy.

Khandekar Melin J MJ Banks Alexander S AS Laznik-Bogoslavski Dina D White James P JP Choi Jang Hyun JH Kazak Lawrence L Lo James C JC Cohen Paul P Wong Kwok-Kin KK Kamenecka Theodore M TM Griffin Patrick R PR Spiegelman Bruce M BM

Proceedings of the National Academy of Sciences of the United States of America 20180102 3

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 ...[more]

PMID: 29295932

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Project description:DNA damage checkpoints are key guardians of genome integrity. Eukaryotic cells respond to DNA damage by triggering extensive phosphorylation of Rad53/CHK2 effector kinase, whereupon activated Rad53/CHK2 mediates further aspects of checkpoint activation, including cell cycle arrest and transcriptional changes. Budding yeast Candida glabrata, closely related to model eukaryote Saccharomyces cerevisiae, is an opportunistic pathogen characterized by high genetic diversity and rapid emergence of drug-resistant mutants. However, the mechanisms underlying this genetic variability are unclear. We used Western blotting and mass spectrometry to show that, unlike S. cerevisiae, C. glabrata cells exposed to DNA damage did not induce C. glabrata Rad53 (CgRad53) phosphorylation. Furthermore, flow cytometry analysis showed that, unlike S. cerevisiae, C. glabrata cells did not accumulate in S phase upon DNA damage. Consistent with these observations, time-lapse microscopy showed C. glabrata cells continuing to divide in the presence of DNA damage, resulting in mitotic errors and cell death. Finally, transcriptome sequencing (RNAseq) analysis revealed transcriptional rewiring of the DNA damage response in C. glabrata and identified several key protectors of genome stability upregulated by DNA damage in S. cerevisiae but downregulated in C. glabrata, including proliferating cell nuclear antigen (PCNA). Together, our results reveal a noncanonical fungal DNA damage response in C. glabrata, which may contribute to rapidly generating genetic change and drug resistance.IMPORTANCE In order to preserve genome integrity, all cells must mount appropriate responses to DNA damage, including slowing down or arresting the cell cycle to give the cells time to repair the damage and changing gene expression, for example to induce genes involved in DNA repair. The Rad53 protein kinase is a conserved central mediator of these responses in eukaryotic cells, and its extensive phosphorylation upon DNA damage is necessary for its activation and subsequent activity. Interestingly, here we show that in the opportunistic fungal pathogen Candida glabrata, Rad53 phosphorylation is not induced by DNA damage, nor do these cells arrest in S phase under these conditions, in contrast to the closely related yeast Saccharomyces cerevisiae Instead, C. glabrata cells continue to divide in the presence of DNA damage, resulting in significant cell lethality. Finally, we show that a number of genes involved in DNA repair are strongly induced by DNA damage in S. cerevisiae but repressed in C. glabrata Together, these findings shed new light on mechanisms regulating genome stability in fungal pathogens.

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Noncanonical agonist PPAR? ligands modulate the response to DNA damage and sensitize cancer cells to cytotoxic chemotherapy.

Publications

Noncanonical agonist PPARγ ligands modulate the response to DNA damage and sensitize cancer cells to cytotoxic chemotherapy.

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