Functional characterization of peroxisome proliferator‐activated receptor‐β/δ expression in colon cancer

Abstract

This study critically examined the role of PPARβ/δ in colon cancer models. Expression of PPARβ/δ mRNA and protein was lower and expression of CYCLIN D1 protein higher in human colon adenocarcinomas compared to matched non-transformed tissue. Similar results were observed in colon tumors from Apc+/Min-FCCC mice compared to control tissue. Dietary administration of sulindac to Apc+/Min-FCCC mice had no influence on expression of PPARβ/δ in normal colon tissue or colon tumors. Cleaved poly (ADP-ribose) polymerase (PARP) was either increased or unchanged, while expression of 14-3-3ε was not influenced in human colon cancer cell lines cultured with the PPARβ/δ ligand GW0742 under conditions known to increase apoptosis. While DLD1 cells exhibited fewer early apoptotic cells after ligand activation of PPARβ/δ following treatment with hydrogen peroxide, this change was associated with an increase in late apoptotic/necrotic cells, but not an increase in viable cells. Stable over-expression of PPARβ/δ in human colon cancer cell lines enhanced ligand activation of PPARβ/δ and inhibition of clonogenicity in HT29 cells. These studies are the most quantitative to date to demonstrate that expression of PPARβ/δ is lower in human and Apc+/Min-FCCC mouse colon tumors than in corresponding normal tissue, consistent with the finding that increasing expression and activation of PPARβ/δ in human colon cancer cell lines inhibits clonogenicity. Because ligand-induced attenuation of early apoptosis can be associated with more late, apoptotic/necrotic cells, but not more viable cells, these studies illustrate why more comprehensive analysis of PPARβ/δ-dependent modulation of apoptosis is required in the future.

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).…”

Metastasis regulation by PPARD expression in cancer cells

“…Several groups have reported that PPARD is upregulated in various human cancers, including colorectal, pancreatic, and lung cancer (5)(6)(7)(8)67), but others have reported contradictory findings (68). The present study's findings show that PPARD was upregulated in colorectal tumors in one of the largest cohorts of colorectal cancer patients yet studied.…”

β-Catenin and Peroxisome Proliferator-activated Receptor-δ Coordinate Dynamic Chromatin Loops for the Transcription of Vascular Endothelial Growth Factor A Gene in Colon Cancer Cells

“…Complex networks with other signaling pathways could provide a way to reconcile contradictory results from different systems (25,56,57). Interplay with ␤-catenin signaling might be reasonable, because of cancerspecific activation of ␤-catenin (50,58,59), association with PPAR-␦ overexpression (26,60,61), and cross-talk between TCF/␤-catenin signaling and PPAR expression and activity (62, 63). Here, we provide evidence that PPAR-␦ acts on the VEGFA gene along with ␤-catenin by regulating chromatin loops.…”