TY - JOUR
T1 - Nuclear factor-κB p65/relA silencing induces apoptosis and increases gemcitabine effectiveness in a subset of pancreatic cancer cells
AU - Pan, Xue
AU - Arumugam, Thiruvengadam
AU - Yamamoto, Tameyoshi
AU - Levin, Pavel A.
AU - Ramachandran, Vijaya
AU - Ji, Baoan
AU - Lopez-Berestein, Gabriel
AU - Vivas-Mejia, Pablo E.
AU - Sood, Anil K.
AU - McConkey, David J.
AU - Logsdon, Craig D.
PY - 2008/12/15
Y1 - 2008/12/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-08-1539
DO - 10.1158/1078-0432.CCR-08-1539
M3 - Article
C2 - 19088029
AN - SCOPUS:58149359830
SN - 1078-0432
VL - 14
SP - 8143
EP - 8151
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -