Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC‐1 cells through DR3‐mediated inhibition of NF‐κB

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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. © 2009 UICC