Journal
ONCOGENE
Volume 33, Issue 46, Pages 5348-5359Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2013.477
Keywords
peroxisome proliferator-activated receptor-beta/delta; HRAS-induced senescence; mechanisms of senescence; inhibition of tumorigenesis
Funding
- National Institutes of Health [CA124533, CA141029, CA140369, AA018863, CA122109, CA117957]
- National Cancer Institute Intramural Research Program [ZIABC005561, ZIABC005562, ZIABC005708]
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Peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) inhibits skin tumorigenesis through mechanisms that may be dependent on HRAS signaling. The present study examined the hypothesis that PPAR beta/delta promotes HRAS-induced senescence resulting in suppression of tumorigenesis. PPAR beta/delta 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 PPAR beta/delta. 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 Ppar beta/delta-null cells. Higher PPAR beta/delta expression is also correlated with increased senescence observed in human benign neurofibromas and colon adenoma lesions in vivo. These results demonstrate that PPAR beta/delta promotes senescence to inhibit tumorigenesis and provide new mechanistic insights into HRAS-induced cellular senescence.
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