Abstract
Death receptors of the tumor necrosis factor (TNF) receptor super family have been implicated in constitutive activation of nuclear factor-kappa B (NF-κB) in pancreatic cancer (PaC) cells. In this study, we demonstrate that fisetin, a natural flavonoid, induces apoptosis and inhibits invasion of chemoresistant PaC AsPC-1 cells through suppression of DR3-mediated NF-κB activation. Fisetin treatment resulted in dose-dependent inhibition of PaC cell growth and cell proliferation with concomitant induction of apoptosis. A cDNA array analysis revealed that fisetin modulates expression of more than 20 genes at transcription level with maximum decrease observed in DR3 expression and a parallel increase observed in the expression levels of IκBα, an NF-κB inhibitor. Down-regulation of DR3 in PaC cells was found to down regulate activated pNF-κB/p65, pIkBα/β kinases (pIKK's), MMP9 and XIAP that mostly impart chemoresistance in PaC. Immunoblotting and EMSA analysis showed a marked decrease in pNF-κB and NF-κB DNA binding activity, respectively, with modest decrease in NF-κB promoter activity and significant decrease in MMP9 promoter activity with fisetin treatment. Importantly, consistent with these findings, we further found that transient down-regulation of DR3 by RNA interference significantly augmented fisetin induced changes in cell proliferation, cell invasion and apoptosis paralleled with decrease in pNF-κB, pIKKα/β, MMP9, XIAP and NF-κB DNA binding activity. Blocking of DR3 receptor with an extra cellular domain blocking antibody demonstrated similar effects. These data provide evidence that fisetin could provide a biological rationale for treatment of pancreatic cancer or as an adjuvant with conventional therapeutic regimens.
Original language | English (US) |
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Pages (from-to) | 2465-2473 |
Number of pages | 9 |
Journal | International Journal of Cancer |
Volume | 125 |
Issue number | 10 |
DOIs | |
State | Published - Nov 15 2009 |
Externally published | Yes |
Keywords
- Apoptosis
- DR3
- Fisetin
- Invasion
- Pancreatic cancer