Research article summary (published 13 Nov 2009):

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

Full Abstract

Death receptors of the tumor necrosis factor (TNF) receptor super family have been implicated in constitutive activation of nuclear factor-kappa B (NF-kappaB) 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-kappaB 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 IkappaBalpha, an NF-kappaB inhibitor. Down-regulation of DR3 in PaC cells was found to down regulate activated pNF-kappaB/p65, pIkBalpha/beta kinases (pIKK's), MMP9 and XIAP that mostly impart chemoresistance in PaC. Immunoblotting and EMSA analysis showed a marked decrease in pNF-kappaB and NF-kappaB DNA binding activity, respectively, with modest decrease in NF-kappaB 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-kappaB, pIKKalpha/beta, MMP9, XIAP and NF-kappaB 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.

Author information

Author/s: Murtaza, Imtiyaz (I); Adhami, Vaqar Mustafa (VM); Hafeez, Bilal Bin (BB); Saleem, Mohammad (M); Mukhtar, Hasan (H);

Affiliation: Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA. imz007(-atsign-)rediffmail.com

Grants: R01CA101039 (Agency:NCI NIH HHS) ; R01CA120451 (Agency:NCI NIH HHS) ; R01CA78809 (Agency:NCI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: International journal of cancer. Journal international du cancer (Int J Cancer), published in United States. (Language: eng)

Reference: 2009-Nov; vol 125 (issue 10) : pp 2465-73

Dates: Created 2009/09/28; Completed 2009/11/05;

PMID: 19670328, status: MEDLINE (last retrieval date: 11/5/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Apoptosis - drug effects Blotting, Western Cell Line, Tumor Cell Proliferation - drug effects Drug Resistance, Neoplasm Electrophoretic Mobility Shift Assay Flavonoids - pharmacology Gene Expression Profiling Humans I-kappa B Proteins - metabolism

Matrix Metalloproteinase 9 - metabolism NF-kappa B - antagonists & inhibitors; genetics; metabolism Neoplasm Invasiveness Oligonucleotide Array Sequence Analysis Pancreatic Neoplasms - drug therapy; metabolism; pathology Promoter Regions, Genetic RNA, Small Interfering - pharmacology Receptors, Tumor Necrosis Factor, Member 25 - antagonists & inhibitors; genetics; metabolism Signal Transduction X-Linked Inhibitor of Apoptosis Protein - metabolism

Associated Chemicals: Flavonoids (0) ; I-kappa B Proteins (0) ; NF-kappa B (0) ; RNA, Small Interfering (0) ; Receptors, Tumor Necrosis Factor, Member 25 (0) ; TNFRSF25 protein, human (0) ; X-Linked Inhibitor of Apoptosis Protein (0) ; XIAP protein, human (0) ; NF-kappaB inhibitor alpha (139874-52-5) ; fisetin (528-48-3) ; Matrix Metalloproteinase 9 (EC 3.4.24.35)

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