Nuclear factor-κB p65/relA silencing induces apoptosis and increases gemcitabine effectiveness in a subset of pancreatic cancer cells

Xue Pan, Thiruvengadam Arumugam, Tameyoshi Yamamoto, Pavel A. Levin, Vijaya Ramachandran, Baoan Ji, Gabriel Lopez-Berestein, Pablo E. Vivas-Mejia, Anil K. Sood, David J. McConkey, Craig D. Logsdon

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

Purpose: Nuclear factor κB(NFκB) activity may increase survival and protect cancer cells from chemotherapy. Therefore, NFκB activity may be prognostic, and inhibition of NFκBmay be useful for pancreatic cancer therapy. To test these hypotheses, we examined NFκBactivity and the effects of inhibiting NFκB in several pancreatic cancer cell lines with differing sensitivities to gemcitabine. Experimental Design: Thegemcitabinesensitivity of pancreatic cancer cell lines BxPC-3, L3.6pl, CFPAC-1, MPanc-96, PANC-1, and MIA PaCa-2 were determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and fluorescence-activated cell sorting assays. NFκB levels were determined by electrophoretic mobility shift assay and reporter assays. The effects of gemcitabine on NFκB activity were determined in vitro and in vivo.NFκB was inhibited by silencing of the p65/rel A subunit using small interfering RNA in vitro and by neutral liposomal delivery of small interfering RNA in vivo, and the effects were evaluated on gemcitabine sensitivity. Results: The cell lines L3.6pl, BxPC-3, and CFPAC-1 were sensitive, whereas MPanc-96, PANC-1, and MIA PaCa-2 were resistant to gemcitabine. No significant correlation was observed between basal NFκB activity and gemcitabine sensitivity. Gemcitabine treatment did not activate NFκB either in vitro or in vivo. Silencing of p65/relA induced apoptosis and increased gemcitabine killing of all gemcitabine-sensitive pancreatic cancer cells. No significant effects, however, were observed on gemcitabine-resistant pancreatic cancer cell lines either in vitro or in vivo. Conclusions: NFκB activity did not correlate with sensitivity to gemcitabine. Silencing of p65/rel A was effective alone and in combination with gemcitabine in gemcitabine-sensitive but not gemcitabine-resistant pancreatic cancer cells. Thus, NFκB may be a useful therapeutic target for a subset of pancreatic cancers.

Original languageEnglish (US)
Pages (from-to)8143-8151
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number24
DOIs
StatePublished - Dec 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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