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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.

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Acknowledgements

We gratefully acknowledge Drs Andrew Billin and Timothy Willson for providing the GW0742, the Center for Quantitative Cell Analysis and the Genomic Core Facility at the Huck Institutes of Life Sciences of The Pennsylvania State University for their technical support with flow cytometry and data analysis. This work was supported by the National Institutes of Health (CA124533, CA141029, CA140369 and AA018863 to JMP; CA122109 and CA117957 to ABG) and the National Cancer Institute Intramural Research Program (ZIABC005561, ZIABC005562 and ZIABC005708 to FJG) .

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Zhu, B., Ferry, C., Blazanin, N. et al. PPARβ/δ promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling. Oncogene 33, 5348–5359 (2014). https://doi.org/10.1038/onc.2013.477

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