Noncanonical agonist PPARγ ligands modulate the response to DNA damage and sensitize cancer cells to cytotoxic chemotherapy
Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that plays a central role in the formation of adipose tissue. We show that phosphorylation of a single amino acid of PPARγ alters the response of cells to DNA damaging agents, including multiple types of chemotherapy. Noncanonical agonist PPARγ ligands that block PPARγ phosphorylation sensitize a variety of cancer cell types to these chemotherapeutic agents in vitro and in vivo. We show that PPARγ interacts with the tumor-suppressor p53 in a manner dependent on PPARγ phosphorylation at S273. These data strongly suggest that noncanonical agonist PPARγ ligands, which lack many of the known side effects of classic agonists, should be explored for clinical use in combination with traditional chemotherapy for a variety of malignancies.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 02, 2018
- Source ID
- 10.1073/pnas.1717776115
Entities
People
- Alexander S. Banks
- Bruce M. Spiegelman
- Dina Laznik-bogoslavski
- James C. Lo
- James P. White
- Jang Hyun Choi
- Kwok-kin Wong
- Lawrence Kazak
- Melin J. Khandekar
- Patrick R Griffin
- Paul Cohen
- Theodore M. Kamenecka
Organizations
- Congressionally Directed Medical Research Programs
- Dana–Farber Cancer Institute
- Freedom Together Foundation
- Harvard Medical School
- Massachusetts General Hospital
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases
- Scripps Research