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

Imtiyaz Murtaza, Vaqar Mustafa Adhami, Bilal Hafeez, Mohammad Saleem, Hasan Mukhtar

Research output: Contribution to journalArticle

75 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2465-2473
Number of pages9
JournalInternational Journal of Cancer
Volume125
Issue number10
DOIs
StatePublished - Nov 15 2009

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NF-kappa B
Pancreatic Neoplasms
Flavonoids
Down-Regulation
Apoptosis
Receptors, Tumor Necrosis Factor, Member 25
Cell Proliferation
eIF-2 Kinase
Death Domain Receptors
Blocking Antibodies
Tumor Necrosis Factor Receptors
DNA
RNA Interference
Oligonucleotide Array Sequence Analysis
Immunoblotting
fisetin
Phosphotransferases
Growth
Genes

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

Cite this

Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3-mediated inhibition of NF-κB. / Murtaza, Imtiyaz; Adhami, Vaqar Mustafa; Hafeez, Bilal; Saleem, Mohammad; Mukhtar, Hasan.

In: International Journal of Cancer, Vol. 125, No. 10, 15.11.2009, p. 2465-2473.

Research output: Contribution to journalArticle

Murtaza, Imtiyaz ; Adhami, Vaqar Mustafa ; Hafeez, Bilal ; Saleem, Mohammad ; Mukhtar, Hasan. / Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3-mediated inhibition of NF-κB. In: International Journal of Cancer. 2009 ; Vol. 125, No. 10. pp. 2465-2473.
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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.",
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AB - 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.

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