Modulation of transcription by the peroxisome proliferator-activated receptor δ–binding RNA aptamer in colon cancer cells

Abstract

Peroxisome proliferator-activated receptor δ (PPAR-δ), one of three PPAR subtypes, is a lipid-sensing nuclear receptor that has been implicated in multiple processes, including inflammation and cancer. To directly establish the role of PPAR-δ in colon cancer development and progression, we selected high-affinity RNA aptamers and expressed them in several colon cancer cell lines. Nuclear-expressed aptamers efficiently inhibited PPAR-δ-dependent transcription from a synthetic peroxisome proliferator response element-driven luciferase reporter. PPAR-δ-specific aptamers suppressed transcription from natural promoters of vascular endothelial cell growth factor-A and cyclooxygenase-2. Moreover, vascular endothelial cell growth factor-A and cyclooxygenase-2 mRNA levels were significantly reduced by the PPAR-δ-specific aptamers in colon cancer cells. Most significantly, HCT116 colon cancer cells with high-level expression of PPAR-δ-specific aptamers exhibited a striking loss of tumorigenic potential. Further study on these RNA aptamers could provide an opportunity to modulate PPAR-δ-mediated colon cancer development and progression. Taken together, our results establish an important role for PPAR-δ in transcription of tumorpromoting genes, which can be specifically modulated by high-affinity RNA intramers in colon cancer cells. The RNA intramers may be further developed as specific inhibitors for cancer therapeutic strategies. [Mol Cancer Ther 2009;8(9):2664-73]

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.…”

The Role of Peroxisome Proliferator-Activated Receptors in Colorectal Cancer

“…Another related mechanism is derived from the observation that ligand activation of PPAR β / δ increases the expression of VEGF through a PPAR β / δ -dependent mechanism, causing increased phosphorylation of AKT, which promotes cell survival by blocking apoptosis [127]. In addition, Kwak et al [128] demonstrated that PPAR β / δ -binding aptamers suppressed transcription from natural promoters of VEGF-A and COX-2 and inhibited tumorigenic potential of colon-cancer cells. These data suggest that PPAR β / δ play an important role in transcription of tumor-promoting genes such as VEGF-A and COX-2.…”

PPARδ Induces Estrogen Receptor-Positive Mammary Neoplasia through an Inflammatory and Metabolic Phenotype Linked to mTOR Activation

“…GW and related agonists enhance adenoma size and angiogenesis in APC min mice (9, 10) and stimulate the growth of several lung (11), breast and prostate cancer cell lines (12, 13), although results to the contrary have also been reported (14). Conversely, disruption of PPARδ expression in colon cancer cells by somatic cell knockout (15) or RNA aptamers (16) inhibited tumor cell growth. These findings are consistent with those demonstrating that homozygous deletion of PPARδ reduces tumorigenesis in MMTV-Cox2 mice (17), intestinal adenomas in APC min mice (18), colon carcinogenesis (19) and pancreatic tumor xenograft growth and angiogenesis in stromal tissue (20).…”