Leucine-zipper protein, LDOC1, inhibits NF-kappaB activation and sensitizes pancreatic cancer cells to apoptosis.

We have isolated a novel gene, LDOC1, which encodes for a leucine zipper protein that was downregulated in a series of human pancreatic cancer cell lines but was expressed in corresponding normal tissues. We report the initial characterization of LDOC1 as a novel regulator of the transcriptional response mediated by the nuclear factor kappa B (NF-kappaB). Transient expression of LDOC1 significantly inhibited the luciferase activity in LDOC1-negative BxPC-3 pancreatic cancer cell line transfected with the NF-kappaB reporter plasmid, activated with mitogen-activated protein kinase/ERK kinase kinase-1 (MEEK). LDOC1, however, does not affect p53, AP1 and CRE-dependent reporter gene expression. The activation of NF-kappaB through ligand-induced stimulation by tumor necrosis factor-alpha (TNF-alpha) or phorbol 12-myristate 13-acetate (PMA) was also inhibited by transient expression of LDOC1 in a dose dependent manner. To determine the growth effect of LDOC1 expression on cancer cells, BxPC-3 cells were stably transfected with LDOC1 cDNA. Viability studies demonstrated that TNF-alpha or PMA-induced antiproliferative effects were significantly enhanced by stable transfection of cells with LDOC1. These observations suggest that LDOC1 is a novel regulator of NF-kappaB that can affect the PMA or TNF-alpha-mediated pathway to apoptosis through inhibition of NF-kappaB activation in BxPC3 pancreatic cancer cells. Copyright 2003 Wiley-Liss, Inc.