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Pleotropic effects of PPARD accelerate colorectal tumor progression and invasion
- Publication Year :
- 2018
- Publisher :
- Cold Spring Harbor Laboratory, 2018.
-
Abstract
- Colorectal carcinogenesis (CRC) progression requires additional molecular mechanisms to APC mutations/aberrant β-catenin signaling. PPARD is a druggable ligand-activated nuclear receptor that regulates essential genes involved in cell fate. PPARD is upregulated in intestinal epithelial cells (IECs) of human colorectal adenomas and adenocarcinomas. The mechanistic significance of PPARD upregulation in CRC remains unknown. Here we show that targeted PPARD overexpression in IECs of mice strongly augmented β-catenin activation via BMP7/TAK1 signaling, promoted intestinal tumorigenesis in Apcmin mice, and accelerated CRC progression and invasiveness in mice with IEC-targeted ApcΔ580 mutation. Human CRC invasive fronts had higher PPARD expression than their paired adenomas. A PPARD agonist (GW501516) enhanced APCΔ580 mutation-driven CRC, while a PPARD antagonist (GSK3787) suppressed it. Functional proteomics analyses and subsequent validation studies uncovered PPARD upregulation of multiple pro-invasive pathways that drive CRC progression (e.g. PDGFRβ, AKT1, CDK1 and EIF4G1). Our results identify novel mechanisms by which PPARD promotes CRC invasiveness and provide the rational for the development of PPARD antagonists to suppress CRC.
- Subjects :
- Agonist
0303 health sciences
Cyclin-dependent kinase 1
Mutation
medicine.drug_class
AKT1
Biology
medicine.disease
medicine.disease_cause
digestive system diseases
3. Good health
GW501516
Bone morphogenetic protein 7
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Nuclear receptor
030220 oncology & carcinogenesis
Cancer research
medicine
030304 developmental biology
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....a816dd666efbccfe4ea8d9ac8e5644b6