Leucine‐zipper protein, LDOC1, inhibits NF‐κB activation and sensitizes pancreatic cancer cells to apoptosis

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Abstract
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‐κB). Transient expression of LDOC1 significantly inhibited the luciferase activity in LDOC1‐negative BxPC‐3 pancreatic cancer cell line transfected with the NF‐κB 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‐κB through ligand‐induced stimulation by tumor necrosis factor‐α (TNF‐α) 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‐α 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‐κB that can affect the PMA or TNF‐α‐mediated pathway to apoptosis through inhibition of NF‐κB activation in BxPC3 pancreatic cancer cells.