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.

Peroxisome Proliferator-activated Receptor-D (PPARD) Coordinates Mouse Spermatogenesis by Modulating Extracellular Signal-regulated Kinase (ERK)-dependent Signaling

“…Moreover, knocking down expression of PPARD in TM4 mouse Sertoli cells mitigated these changes in expression of p27, cyclin D1, and cyclin D2. This is consistent with previous findings that ligand activation of PPARD suppresses cyclin D1 or increases p27 expression, causing inhibition of cell proliferation in cancer cells and primary keratinocytes (16,46,47). Furthermore, the present studies also demonstrated that ligand activation of PPARD alters expression of cell cycle regulators by modulating ERK activation in Sertoli cells in vivo and in vitro, consistent with previous studies (16, 48 -50).…”

“…Fluorescence signals were detected using excitation/emission wavelengths of 499/519 or 652/668 nm. All sections were imaged using laser-scanning confocal microscopy as described previously (16).…”

The Nuclear Receptor Peroxisome Proliferator-activated Receptor-β/δ (PPARβ/δ) Promotes Oncogene-induced Cellular Senescence through Repression of Endoplasmic Reticulum Stress

“…This is consistent with relatively lower H-RAS-induced ER stress and lower p-AKT in H-RAS-expressing wild-type keratinocytes compared with H-RAS-expressing Ppar␤/␦-null cells (11). Similarly, this is consistent with relatively higher H-RAS-induced ER stress and higher p-AKT in H-RAS-expressing Ppar␤/␦-null keratinocytes compared with H-RAS-expressing wild-type keratinocytes (11).…”

“…Senescence-PPAR␤/␦ promotes H-RAS-induced cellular senescence (11). The relatively lower level of ER stress observed in H-RAS-expressing wild-type keratinocytes in the present study correlates with relatively higher levels of senescence previously observed (11).…”

“…Complete Carcinogenesis Bioassay-A complete carcinogenesis bioassay was performed as previously described (11).…”