PURPOSE: Nuclear factor kappaB (NFkappaB) activity may increase survival and protect cancer cells from chemotherapy. Therefore, NFkappaB activity may be prognostic, and inhibition of NFkappaB may be useful for pancreatic cancer therapy. To test these hypotheses, we examined NFkappaB activity and the effects of inhibiting NFkappaB in several pancreatic cancer cell lines with differing sensitivities to gemcitabine. EXPERIMENTAL DESIGN: The gemcitabine sensitivity 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. NFkappaB levels were determined by electrophoretic mobility shift assay and reporter assays. The effects of gemcitabine on NFkappaB activity were determined in vitro and in vivo. NFkappaB was inhibited by silencing of the p65/relA 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 NFkappaB activity and gemcitabine sensitivity. Gemcitabine treatment did not activate NFkappaB 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: NFkappaB activity did not correlate with sensitivity to gemcitabine. Silencing of p65/relA was effective alone and in combination with gemcitabine in gemcitabine-sensitive but not gemcitabine-resistant pancreatic cancer cells. Thus, NFkappaB may be a useful therapeutic target for a subset of pancreatic cancers.
PURPOSE:Nuclear factor kappaB (NFkappaB) activity may increase survival and protect cancer cells from chemotherapy. Therefore, NFkappaB activity may be prognostic, and inhibition of NFkappaB may be useful for pancreatic cancer therapy. To test these hypotheses, we examined NFkappaB activity and the effects of inhibiting NFkappaB in several pancreatic cancer cell lines with differing sensitivities to gemcitabine. EXPERIMENTAL DESIGN: The gemcitabine sensitivity 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. NFkappaB levels were determined by electrophoretic mobility shift assay and reporter assays. The effects of gemcitabine on NFkappaB activity were determined in vitro and in vivo. NFkappaB was inhibited by silencing of the p65/relA 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 NFkappaB activity and gemcitabine sensitivity. Gemcitabine treatment did not activate NFkappaB 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:NFkappaB activity did not correlate with sensitivity to gemcitabine. Silencing of p65/relA was effective alone and in combination with gemcitabine in gemcitabine-sensitive but not gemcitabine-resistant pancreatic cancer cells. Thus, NFkappaB may be a useful therapeutic target for a subset of pancreatic cancers.
Authors: Susanne Müerköster; Alexander Arlt; Maike Witt; André Gehrz; Sieglinde Haye; Christina March; Frauke Grohmann; Kai Wegehenkel; Holger Kalthoff; Ulrich R Fölsch; Heiner Schäfer Journal: Int J Cancer Date: 2003-04-20 Impact factor: 7.396
Authors: Qiang G Dong; Guido M Sclabas; Shuichi Fujioka; Christian Schmidt; Bailu Peng; TianAi Wu; Ming-Sound Tsao; Douglas B Evans; James L Abbruzzese; Timothy J McDonnell; Paul J Chiao Journal: Oncogene Date: 2002-09-19 Impact factor: 9.867
Authors: Susanne Liptay; Christoph K Weber; Leopold Ludwig; Martin Wagner; Guido Adler; Roland M Schmid Journal: Int J Cancer Date: 2003-07-20 Impact factor: 7.396
Authors: Geou-Yarh Liou; Heike Döppler; Brian Necela; Brandy Edenfield; Lizhi Zhang; David W Dawson; Peter Storz Journal: Cancer Discov Date: 2014-10-31 Impact factor: 39.397
Authors: Federico Innocenti; Kouros Owzar; Nancy L Cox; Patrick Evans; Michiaki Kubo; Hitoshi Zembutsu; Chen Jiang; Donna Hollis; Taisei Mushiroda; Liang Li; Paula Friedman; Liewei Wang; Dylan Glubb; Herbert Hurwitz; Kathleen M Giacomini; Howard L McLeod; Richard M Goldberg; Richard L Schilsky; Hedy L Kindler; Yusuke Nakamura; Mark J Ratain Journal: Clin Cancer Res Date: 2011-12-05 Impact factor: 12.531
Authors: Michael P Kim; Mark J Truty; Woonyoung Choi; Ya'an Kang; Xavier Chopin-Lally; Gary E Gallick; Huamin Wang; David J McConkey; Rosa Hwang; Craig Logsdon; James Abbruzzesse; Jason B Fleming Journal: Ann Surg Oncol Date: 2011-06-24 Impact factor: 5.344
Authors: Prakash Radhakrishnan; Vashti C Bryant; Elizabeth C Blowers; Rajkumar N Rajule; Nagsen Gautam; Muhammad M Anwar; Ashley M Mohr; Paul M Grandgenett; Stephanie K Bunt; Jamie L Arnst; Subodh M Lele; Yazen Alnouti; Michael A Hollingsworth; Amarnath Natarajan Journal: Clin Cancer Res Date: 2013-02-26 Impact factor: 12.531