Role of peroxisome proliferator-activated receptor β/δ and B-cell lymphoma-6 in regulation of genes involved in metastasis and migration in pancreatic cancer cells

Jeffrey D. Coleman, Jerry T. Thompson, Russell W. Smith, Bogdan Prokopczyk, John P. Vanden Heuvel

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

PPAR β /δ is a ligand-activated transcription factor that regulates various cellular functions via induction of target genes directly or in concert with its associated transcriptional repressor, BCL-6. Matrix remodeling proteinases are frequently over-expressed in pancreatic cancer and are involved with metastasis. The present study tested the hypothesis that PPARβ/δ is expressed in human pancreatic cancer cells and that its activation could regulate MMP-9, decreasing cancer cells ability to transverse the basement membrane. In human pancreatic cancer tissue there was significantly higher expression of MMP-9 and PPARβ/δ, and lower levels of BCL-6 mRNA. PPARβ/δ activation reduced the TNFα-induced expression of various genes implicated in metastasis and reduced the invasion through a basement membrane in cell culture models. Through the use of short hairpin RNA inhibitors of PPARβ/δ, BCL-6, and MMP-9, it was evident that PPARβ/δ was responsible for the ligand-dependent effects whereas BCL-6 dissociation upon GW501516 treatment was ultimately responsible for decreasing MMP-9 expression and hence invasion activity. These results suggest that PPARβ/δ plays a role in regulating pancreatic cancer cell invasion through regulation of genes via ligand-dependent release of BCL-6 and that activation of the receptor may provide an alternative therapeutic method for controlling migration and metastasis.

Original languageEnglish (US)
Article number121956
JournalPPAR Research
DOIs
StatePublished - 2013

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Pharmacology (medical)

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