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Oncogene. 2014 Nov 13;33(46):5348-59. doi: 10.1038/onc.2013.477. Epub 2013 Nov 11.

PPARβ/δ promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling.

Author information

1
Department of Veterinary and Biomedical Sciences, The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA.
2
Preclinical Research Center, Chemon, Yongin-Si, Korea.
3
Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, USA.

Abstract

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) inhibits skin tumorigenesis through mechanisms that may be dependent on HRAS signaling. The present study examined the hypothesis that PPARβ/δ promotes HRAS-induced senescence resulting in suppression of tumorigenesis. PPARβ/δ expression increased p-ERK and decreased p-AKT activity. Increased p-ERK activity results from the dampened HRAS-induced negative feedback response mediated in part through transcriptional upregulation of RAS guanyl-releasing protein 1 (RASGRP1) by PPARβ/δ. Decreased p-AKT activity results from repression of integrin-linked kinase (ILK) and phosphoinositide-dependent protein kinase-1 (PDPK1) expression. Decreased p-AKT activity in turn promotes cellular senescence through upregulation of p53 and p27 expression. Both over-expression of RASGRP1 and shRNA-mediated knockdown of ILK partially restore cellular senescence in Pparβ/δ-null cells. Higher PPARβ/δ expression is also correlated with increased senescence observed in human benign neurofibromas and colon adenoma lesions in vivo. These results demonstrate that PPARβ/δ promotes senescence to inhibit tumorigenesis and provide new mechanistic insights into HRAS-induced cellular senescence.

PMID:
24213576
PMCID:
PMC4017002
DOI:
10.1038/onc.2013.477
[Indexed for MEDLINE]
Free PMC Article

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