Therapeutic potential of GW501516 and the role of Peroxisome proliferator-activated receptor β/δ and B-cell lymphoma 6 in inflammatory signaling in human pancreatic cancer cells

Abstract

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a member of the nuclear receptor superfamily and a ligand-activated transcription factor that is involved in the regulation of the inflammatory response via activation of anti-inflammatory target genes and ligand-induced disassociation with the transcriptional repressor B-cell lymphoma 6 (BCL6). Chronic pancreatitis is considered to be a significant etiological factor for pancreatic cancer development, and a better understanding of the underlying mechanisms of the transition between inflammation and carcinogenesis would help further elucidate chemopreventative options. The aim of this study was to determine the role of PPARβ/δ and BCL6 in human pancreatic cancer of ductal origin, as well as the therapeutic potential of PPARβ/δ agonist, GW501516. Over-expression of PPARβ/δ inhibited basal and TNFα-induced Nfkb luciferase activity. GW501516-activated PPARβ/δ suppressed TNFα-induced Nfkb reporter activity. RNAi knockdown of Pparb attenuated the GW501516 effect on Nfkb luciferase, while knockdown of Bcl6 enhanced TNFα-induced Nfkb activity. PPARβ/δ activation induced expression of several anti-inflammatory genes in a dose-dependent manner, and GW501516 inhibited Mcp1 promoter-driven luciferase in a BCL6-dependent manner. Several pro-inflammatory genes were suppressed in a BCL6-dependent manner. Conditioned media from GW501516-treated pancreatic cancer cells suppressed pro-inflammatory expression in THP-1 macrophages as well as reduced invasiveness across a basement membrane. These results demonstrate that PPARβ/δ and BCL6 regulate anti-inflammatory signaling in human pancreatic cancer cells by inhibiting NFκB and pro-inflammatory gene expression, and via induction of anti-inflammatory target genes. Activation of PPARβ/δ may be a useful target in pancreatic cancer therapeutics.

Molecular and nanoscale evaluation of N-cadherin expression in invasive bladder cancer cells under control conditions or GW501516 exposure

“…Unliganded PPARβ/δ is known to be associated with the transcriptional repressor BCL6 (B-cell lymphoma 6), a mechanism responsible for the anti-inflammatory properties of this receptor [40] and BCL6 is an inhibitor of NFκB activity [41]. As demonstrated in pancreatic cancer cells upon binding of GW501516, PPARβ/δ decreased TNFα (Tumor Necrosis Factor α)-induced NFκB activity leading to the induction of anti-inflammatory genes and consequently to the inhibition of pro-inflammatory genes through the dissociation of BCL6 [42]. Further investigations are needed to clarify the negative regulation of cdh2 mediated by GW501516 in T24 cells.…”

PPAR-delta acts as a metabolic master checkpoint for metastasis in pancreatic cancer

“…Even more importantly, poor patient outcome, including reduced metastasis-free survival correlated with PPARD expression in various cancer types (Abdollahi et al, 2007;Zuo et al, 2017). However, while accumulating evidence suggest that PPAR-δ also promotes tumor progression and metastasis in PDAC (Liu et al, 2020;Sanford-Crane et al, 2020;Zuo et al, 2017), other reports have questioned these finding (Coleman et al, 2013;Smith et al, 2016).…”

A new trend in use of performance enhancing drugs in CrossFit®

“…Lze se setkat i s jinými obchodními názvy, jedná se však o stejnou účinnou látku. Většina studií byla realizovaná na myších, dále se také jednalo o výzkumy in vitro (Kino, Rice, & Chrousos, 2007;Smith, Coleman, Thompson, & Vanden Heuvel, 2016). Pouze tři studie sledovaly účinky na lidském vzorku (Sprecher et al, 2007;Risérus et al, 2008;Olson, Pearce, Jones, & Sprecher, 2012).…”

“…Vliv na nádorová onemocnění není jednotný, prokázaly se protichůdné efekty (Yin et al, 2005;Yuan et al, 2013, Smith et al, 2016. Závěry se však kloní k bezpečnosti z pohledu karcinogenity.…”