Crosstalk between the 5-lipoxygnease and EGF-MAPK pathway in pancreatic cancer

The signal molecules that regulate pancreatic cancer growth are still poorly understood. We have previously reported that 5-lipoxygenase not expressed in normal pancreatic ductal cells, but was markedly upregulated and involved cell proliferation and survival in human pancreatic cancer. Pancreatic cancer cells produce a large amount of growth factors, which are important for maintaining pancreatic cancer cell proliferation and survival. The current study investigated the interaction between epidermal growth factor (EGF) and 5-lipoxygenase in controlling pancreatic cancer cell proliferation. EGF increased both 5-lipoxygenase mRNA and protein expression in pancreatic cancer cells; the increased 5-lipoxygenase expression was mediated, at least partially through enhancing 5-lipoxygnease transcription as demonstrated by increased 5-lipoxygenase promoter activity following EGF treatment. On the other hand, blockade of 5-lipoxygnease with a 5-lipoxygenase inhibitor, Rev5901, inhibited EGF-induced pancreatic cancer cell proliferation. It appears that the synergistic interaction between EGF and 5-lipoxygease is critical for P42/44 MAPK activation and pancreatic cancer cell proliferation since EGF-induced P42/44 MAPK activation and cell proliferation is attenuated by blockage of 5-lipoxygenase. In summary, the current study shows that the crosstalk between 5-lipoxygeanse and EGF signaling pathways may be critical for pancreatic cancer cell proliferation.