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

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.

• Authors: B Zhu, C H Ferry, N Blazanin, M T Bility, C Khozoie, B-H Kang, A B Glick, F J Gonzalez, J M Peters
• Journal: Oncogene (Oncogene) Vol. 33 Issue 46 Pg. 5348-59 (Nov 13 2014) ISSN: 1476-5594 [Electronic] England
• PMID: 24213576 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• PPAR delta
• PPAR-beta
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• ras Proteins

Topics

• Aging (genetics, metabolism)
• Animals
• Blotting, Western
• Carcinogenesis (genetics, metabolism)
• Cells, Cultured
• Cellular Senescence (genetics)
• Female
• HEK293 Cells
• Humans
• Keratinocytes (cytology, metabolism)
• Mice
• Mice, Knockout
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• NIH 3T3 Cells
• PPAR delta (genetics, metabolism)
• PPAR-beta (genetics, metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Skin Neoplasms (genetics, metabolism, pathology)
• ras Proteins (genetics, metabolism)