Pancreatic adenocarcinoma is the fifth leading cause of adult cancer mortality in the United States, and treatments for this cancer are largely ineffective. However, a better understanding of the molecular basis of pancreatic tumorigenesis may aid in the design of more effective therapeutic strategies. They plan to improve this understanding by studying Rel/NF-kB. This family of transcription factors is involved in the differentiation of immune cells and organs, tumorigenic transformation, embryonic development, and apoptosis. In previous studies, they detected constitutively active Rel/NFkB in 14 of 20 (70 percent) pancreatic adenocarcinomas but not in normal pancreas. They also detected it in 7 of 11 (64 percent) human pancreatic tumor cell lines. The activated Rel/NFkB may inhibit apoptotic stimuli through induction of bcl-2 gene expression. So, they hypothesize that (1) constitutively activated RelA plays a critical role in pancreatic tumorigenesis and/or inhibits pro-apoptotic stimulation by inducing the expression of downstream target genes and (2) inhibition of RelA plays a critical role in pancreatic tumorigenesis and/or inhibits pro-apoptotic stimulation by inducing the expression of downstream target genes and (2) inhibition of RelA activity may repress tumor formation and/or render these tumor cells more susceptible to apoptosis induced by anticancer drugs. To test the hypothesis, they will specific inhibit or activate Rel/NFkB to determine the significance of this alteration for growth and apoptosis, to determine if bcl-2 is the downstream target gene regulated by Rel/NFkB, and to determine if MAP kinases constitute the upstream signal transduction pathway for Rel/NFkB activation. The studies may lead to the development of specific inhibitors of Rel/NFkB for use in novel therapies for pancreatic cancers.
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